Pyrido[4,3-B]indoles and methods of use

ABSTRACT

New heterocyclic compounds that may be used to modulate a histamine receptor in an individual are described. Pyrido[4,3-b]indoles are described, as are pharmaceutical compositions comprising the compounds and methods of using the compounds in a variety of therapeutic applications, including the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder and/or a neuronal disorder.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application is submitted under 35 U.S.C. §371 as a U.S.national stage application of International Application No.PCT/US2010/033055, filed on Apr. 29, 2010, which claims priority benefitof Indian Patent Application No. 1135/MUM/2009, filed Apr. 29, 2009, andU.S. Provisional Patent Application No. 61/181,259, filed May 26, 2009,the disclosures of each of which are hereby incorporated herein byreference in their entireties.

STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH

Not applicable.

BACKGROUND OF THE INVENTION

Neurotransmitters such as histamine, serotonin, dopamine andnorepinephrine mediate a large number of processes in the centralnervous system (CNS) as well as outside the CNS. Abnormalneurotransmitter levels are associated with a wide variety of diseasesand conditions including, but not limited to, Alzheimer's disease,Parkinson's Disease, autism, Guillain-Barré syndrome, mild cognitiveimpairment, schizophrenia (such as cognitive impairment associated withschizophrenia (CIAS), positive symptoms, disorganized symptoms, andnegative symptoms of schizophrenia), anxiety, multiple sclerosis,stroke, traumatic brain injury, spinal cord injury, diabetic neuropathy,fibromyalgia, bipolar disorders, psychosis, depression,attention-deficit disorder (ADD), attention-deficit hyperactivitydisorder (ADHD) and a variety of allergic diseases. Compounds thatmodulate these neurotransmitters may be useful therapeutics.

Histamine receptors belong to the superfamily of G protein-coupled seventransmembrane proteins. G protein-coupled receptors constitute one ofthe major signal transduction systems in eukaryotic cells. Codingsequences for these receptors, in those regions believed to contributeto the agonist-antagonist binding site, are strongly conserved acrossmammalian species. Histamine receptors are found in most peripheraltissue and within the central nervous system. Compounds capable ofmodulating a histamine receptor may find use in therapy, e.g., histamineantagonists may find use as antihistamines.

Dimebon is a known anti-histamine drug that has also been characterizedas a neuroprotective agent useful to treat, inter alia,neurodegenerative diseases. Dimebon has been shown to inhibit the deathof brain cells (neurons) in preclinical models of Alzheimer's diseaseand Huntington's disease, making it a novel potential treatment forthese and other neurodegenerative diseases. In addition, dimebon hasbeen shown to improve the mitochondrial function of cells in the settingof cellular stress with very high potency. For example, dimebontreatment improved mitochondrial function and increased the number ofsurviving cells after treatment with the cell toxin ionomycin in a dosedependent fashion. Dimebon has also been shown to promote neuriteoutgrowth and neurogenesis, processes important in the formation of newand/or enhanced neuronal cell connections, and evidence of dimebon'spotential for use in additional diseases or conditions. See, e.g., U.S.Pat. Nos. 6,187,785 and 7,071,206 and PCT Patent Application Nos.PCT/US2004/041081, PCT/US2007/020483, PCT/US2006/039077,PCT/US2008/077090, PCT/US2007/020516, PCT/US2007/022645,PCT/US2007/002117, PCT/US2008/006667, PCT/US2007/024626,PCT/US2008/009357, PCT/US2007/024623 and PCT/US2008/008121. Hydrogenatedpyrido[4,3-b]indoles and uses thereof have been disclosed in PCT PatentApplication Nos. PCT/US2008/081390, PCT/US2009/032065, PCT/US2009/038142and PCT/US2009/062869. All references disclosed herein and throughout,such as publications, patents, patent applications and published patentapplications, are incorporated herein by reference in their entireties.

Although dimebon holds great promise as a drug for the treatment ofneurodegenerative diseases and/or diseases in which neurite outgrowthand/or neurogenesis may be implicated in therapy, there remains a needfor new and alternative therapies for the treatment of such diseases orconditions. In addition, there remains a need for new and alternativeantihistamine drugs, preferably ones in which side-effects such asdrowsiness are reduced or eliminated. Compounds that exhibit enhancedand/or more desirable properties than dimebon (e.g., superior safety andefficacy) may find particular use in the treatment of at least thoseindications for which dimebon is believed to be advantageous. Further,compounds that exhibit a different therapeutic profile than dimebon asdetermined, e.g., by in vitro and/or in vivo assays, may find use inadditional diseases and conditions.

BRIEF SUMMARY OF THE INVENTION

Compounds detailed herein are described as histamine receptormodulators. In one aspect, the histamine receptor modulator is acompound that binds to or inhibits binding of a ligand to a histamine(e.g., H₁ and/or H₂ and/or H₃) receptor or mimics an activity of such ahistamine receptor. In some embodiments, the histamine receptormodulator inhibits binding of a ligand by at least about or about anyone of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% asdetermined in the assays described herein. Compositions comprising thecompounds are provided, as are kits comprising the compounds as well asmethods of using and making the compounds. The compounds provided hereinmay find use in treating neurodegenerative diseases. Compounds providedmay also find use in treating diseases and/or conditions in whichmodulation of aminergic G protein-coupled receptors and/or neuriteoutgrowth may be implicated in therapy. Compounds disclosed herein mayfind use in the methods disclosed herein, including use in treating,preventing, delaying the onset and/or delaying the development of acognitive disorder, psychotic disorder, neurotransmitter-mediateddisorder and/or a neuronal disorder in an individual in need thereof,such as humans.

Compounds of the formula (A) are detailed herein, including saltsthereof, such as a pharmaceutically acceptable salt thereof and solvatesof the foregoing.

wherein:

R¹ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

R² is H, hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl, substitutedor unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl, carbonylalkoxy, thiol,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaralkyl, thioalkyl, substituted or unsubstituted amino, acylamino,aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl,sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino oracyl;

X is OH, H, C₁-C₈ unsubstituted alkyl or is taken together with Y toform a cyclic moiety of the formula —OCH₂CH₂O—;

Y is halo, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, C₁-C₈ alkyl substituted with a carbonylalkoxy,carboxyl or acylamino moiety or is taken together with X to form acyclic moiety of the formula —OCH₂CH₂O—; and

R³ is a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl or a substituted or unsubstitutedheterocyclyl;

or a salt or solvate thereof.

Compounds of the formulae (I)-(VII) are also detailed herein:

where R¹, R² and R³ are as defined for formula (A) and R⁴ is anunsubstituted C₁-C₈ alkyl.

Salts of the compounds detailed herein are also described, such as apharmaceutically acceptable salt thereof and solvates of the foregoing.

The invention also includes all salts of compounds referred to herein,such as pharmaceutically acceptable salts. A pharmaceutically acceptablesalt intends ionic interactions and not a covalent bond. As such, anN-oxide is not considered a salt. Examples of pharmaceuticallyacceptable salts include those listed in Berge et al., PharmaceuticalSalts, J. Pharm. Sci. 1977 January; 66(1):1-19. The invention alsoincludes any or all of the stereochemical forms, including anyenantiomeric or diastereomeric forms, of the compounds described. Unlessstereochemistry is explicitly indicated in a chemical structure or name,the structure or name is intended to embrace all possible stereoisomersof a compound depicted. All forms of the compounds are also embraced bythe invention, such as crystalline or non-crystalline forms of thecompounds. Compositions comprising a compound of the invention are alsointended, such as a composition of substantially pure compound,including a specific stereochemical form thereof. Compositionscomprising a mixture of compounds of the invention in any ratio are alsoembraced by the invention, including mixtures of two or morestereochemical forms of a compound of the invention in any ratio, suchthat racemic, non-racemic, enantio-enriched and scalemic mixtures of acompound are embraced, or mixtures thereof.

Compounds of the invention may be presented in the form of chemicalstructures or names. Chemical structures and names have been generatedusing graphical software, e.g., ChemBioDraw Ultra 11.0 (CambridgeSoftCo.), which includes a facility to generate IUPAC-standard names fromChemDraw structures, and vice-versa, based on Beilstein's AutoNomconversion algorithms.

The invention is also directed to pharmaceutical compositions comprisinga compound of the invention and a pharmaceutically acceptable carrier orexcipient. Kits comprising a compound of the invention and instructionsfor use are also embraced by this invention. Compounds as detailedherein or a pharmaceutically acceptable salt thereof are also providedfor the manufacture of a medicament for the treatment of a cognitivedisorder, psychotic disorder, neurotransmitter-mediated disorder or aneuronal disorder.

In one aspect, compounds of the invention are used to treat, prevent,delay the onset and/or delay the development of any one or more of thefollowing: cognitive disorders, psychotic disorders,neurotransmitter-mediated disorders and/or neuronal disorders inindividuals in need thereof, such as humans. In one variation, compoundsof the invention are used to treat, prevent, delay the onset and/ordelay the development of diseases or conditions for which the modulationof an aminergic G protein-coupled receptor is believed to be or isbeneficial. In one variation, compounds of the invention are used totreat, prevent, delay the onset and/or delay the development of any oneor more of diseases or conditions for which neurite outgrowth and/orneurogenesis and/or neurotrophic effects are believed to be or arebeneficial. In another variation, compounds of the invention are used totreat, prevent, delay the onset and/or delay the development of diseasesor conditions for which the modulation of an aminergic G protein-coupledreceptor and neurite outgrowth and/or neurogenesis and/or neurotrophiceffects are believed to be or are beneficial. In one variation, thedisease or condition is a cognitive disorder, psychotic disorder,neurotransmitter-mediated disorder and/or a neuronal disorder.

In another aspect, compounds of the invention are used to improvecognitive function and/or reduce psychotic effects in an individual,comprising administering to an individual in need thereof an amount of acompound described herein or a pharmaceutically acceptable salt thereofeffective to improve cognitive function and/or reduce psychotic effects.

In a further aspect, compounds of the invention are used to stimulateneurite outgrowth and/or promote neurogenesis and/or enhanceneurotrophic effects in an individual comprising administering to anindividual in need thereof an amount of a compound described herein or apharmaceutically acceptable salt thereof effective to stimulate neuriteoutgrowth and/or to promote neurogenesis and/or to enhance neurotrophiceffects. Synapse loss is associated with a variety of neurodegenerativediseases and conditions including Alzheimer's disease, schizophrenia,Huntington's disease, Parkinson's disease, amyotrophic lateralsclerosis, stroke, head trauma and spinal cord injury. Compounds of theinvention that stimulate neurite outgrowth may have a benefit in thesesettings.

In another aspect, compounds described herein are used to modulate anaminergic G protein-coupled receptor comprising administering to anindividual in need thereof an amount of a compound described herein or apharmaceutically acceptable salt thereof effective to modulate anaminergic G protein-coupled receptor. In one variation, a compound ofthe invention modulates at least one of the following receptors:adrenergic receptor (e.g., a_(1D), a_(2A) and/or a_(2B)), serotoninreceptor (e.g., 5-HT_(2A), 5-HT_(2C), 5-HT₆ and/or 5-HT₇), dopaminereceptor (e.g., D_(2L)) and histamine receptor (e.g., H₁, H₂ and/or H₃).In another variation, at least two of the following receptors aremodulated: adrenergic receptor (e.g., a_(1D), a_(2A) and/or a_(2B)),serotonin receptor (e.g., 5-HT_(2A), 5-HT_(2C), 5-HT₆ and/or 5-HT₇),dopamine receptor (e.g., D_(2L)) and histamine receptor (e.g., H₁, H₂and/or H₃). In another variation, at least three of the followingreceptors are modulated: adrenergic receptor (e.g., a_(1D), a_(2A)and/or a_(2B)), serotonin receptor (e.g., 5-HT_(2A), 5-HT_(2C), 5-HT₆and/or 5-HT₇), dopamine receptor (e.g., D_(2L)) and histamine receptor(e.g., H₁, H₂ and/or H₃). In another variation, each of the followingreceptors is modulated: adrenergic receptor (e.g., a_(1D), a_(2A) and/ora_(2B)), serotonin receptor (e.g., 5-HT_(2A), 5-HT_(2C), 5-HT₆ and/or5-HT₇), dopamine receptor (e.g., D_(2L)) and histamine receptor (e.g.,H₁, H₂ and/or H₃). In another variation, at least one of the followingreceptors is modulated: a_(1D), a_(2A), a_(2B), 5-HT_(2A), 5-HT_(2C),5-HT₆, 5-HT₇, D_(2L), H₁, H₂ and H₃. In another variation, at least oneof the following receptors is modulated: a_(1D), a_(2A), a_(2B),5-HT_(2A), 5-HT_(2C), 5-HT₆, 5-HT₇, D₂, H₁, H₂ and H₃. In anothervariation, at least two or three or four or five or six or seven oreight or nine or ten or eleven of the following receptors are modulated:a_(1D), a_(2A), a_(2B), 5-HT_(2A), 5-HT_(2C), 5-HT₆, 5-HT₇, D_(2L), H₁,H₂ and H₃. In another variation, at least two or three or four or fiveor six or seven or eight or nine or ten or eleven of the followingreceptors are modulated: a_(1D), a_(2A), a_(2B), 5-HT_(2A), 5-HT_(2C),5-HT₆, 5-HT₇, D₂, H₁, H₂ and H₃. In a particular variation, at leastdopamine receptor D₂ is modulated. In still another variation, at leastdopamine receptor D_(2L) is modulated. In another particular variation,at least dopamine receptor D₂ and serotonin receptor 5-HT_(2A) aremodulated. In another particular variation, at least dopamine receptorD_(2L) and serotonin receptor 5-HT_(2A) are modulated. In a furtherparticular variation, at least adrenergic receptors a_(1D), a_(2A),a_(2B) and serotonin receptor 5-HT₆ are modulated. In another particularvariation, at least adrenergic receptors a_(1D), a_(2A), a_(2B),serotonin receptor 5-HT₆ and one or more of serotonin receptor 5-HT₇,5-HT_(2A), 5-HT_(2C) and histamine receptor H₁ and H₂ are modulated. Ina further particular variation, histamine receptor H₁ is modulated. Inanother variation, compounds of the invention exhibit any receptormodulation activity detailed herein and further stimulate neuriteoutgrowth and/or neurogenesis and/or enhance neurotrophic effects. Inone variation, compounds detailed herein inhibit binding of a ligand tohistamine receptor H₁ and/or H₂ by less than about 80% as determined bya suitable assay known in the art such as the assays described herein.In another variation, binding of a ligand to histamine receptor H₁and/or H₂ is inhibited by less than about any of 75%, 70%, 65%, 60%,55%, or 50% as determined by a suitable assay known in the art such asthe assays described herein. In a further variation, compounds detailedherein: (a) inhibit binding of a ligand to histamine receptor H₁ and/orH₂ by less than about 80% (which can in different variations be lessthan about any of 75%, 70%, 65%, 60%, 55%, or 50%) as determined by asuitable assay known in the art such as the assays described herein and(b) inhibit binding of a ligand to dopamine receptor D_(2L) by greaterthan about any of 80%, 85%, 90%, 95%, 100% or between about 85% andabout 95% or between about 90% and about 100%, as determined in asuitable assay known in the art such as the assays described herein. Ina further variation, compounds detailed herein: (a) inhibit binding of aligand to histamine receptor H₁ and/or H₂ by less than about 80% (whichcan in different variations be less than about any of 75%, 70%, 65%,60%, 55%, or 50%) as determined by a suitable assay known in the artsuch as the assays described herein and (b) inhibit binding of a ligandto a dopamine receptor D₂ by greater than about any of 80%, 85%, 90%,95%, 100% or between about 85% and about 95% or between about 90% andabout 100%, as determined in a suitable assay known in the art such asthe assays described herein.

The invention is also directed to pharmaceutical compositions comprisinga compound of the invention and a pharmaceutically acceptable carrier orexcipient. Kits comprising a compound of the invention and instructionsfor use are also embraced by this invention.

DETAILED DESCRIPTION OF THE INVENTION Definitions

For use herein, unless clearly indicated otherwise, use of the terms“a”, “an” and the like refers to one or more.

As used herein, reference to “about” a value or parameter hereinincludes (and describes) embodiments that are directed to that value orparameter per se. For example, description referring to “about X”includes description of “X”.

As used herein, the term “aminergic G protein-coupled receptors” refersto a family of transmembrane proteins involved in cellularcommunication. Aminergic G protein coupled receptors are activated bybiogenic amines and represent a subclass of the superfamily of G proteincoupled receptors, which are structurally characterized by seventransmembrane helices. Aminergic G protein-coupled receptors include butare not limited to adrenergic receptors, serotonin receptors, dopaminereceptors, histamine receptors and imidazoline receptors.

As used herein, the term “adrenergic receptor modulator” intends andencompasses a compound that binds to or inhibits binding of a ligand toan adrenergic receptor or reduces or eliminates or increases or enhancesor mimics an activity of an adrenergic receptor. As such, an “adrenergicreceptor modulator” encompasses both an adrenergic receptor antagonistand an adrenergic receptor agonist. In some aspects, the adrenergicreceptor modulator binds to or inhibits binding to a ligand to anα₁-adrenergic receptor (e.g., α_(1A), α_(1B) and/or α_(1D)) and/or aα₂-adrenergic receptor (e.g., α_(2A), α_(2B) and/or α_(2C)) and/orreduces or eliminates or increases or enhances or mimics an activity ofa α₁-adrenergic receptor (e.g., α_(1A), α_(1B) and/or α_(1D)) and/or aα₂-adrenergic receptor (e.g., α_(2A), α_(2B) and/or α_(2C)) in areversible or irreversible manner. In some aspects, the adrenergicreceptor modulator inhibits binding of a ligand by at least about orabout any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or100% as determined in the assays described herein. In some aspects, theadrenergic receptor modulator reduces an activity of an adrenergicreceptor by at least or about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%,80%, 90%, 95% or 100% as compared to the corresponding activity in thesame subject prior to treatment with the adrenergic receptor modulatoror compared to the corresponding activity in other subjects notreceiving the adrenergic receptor modulator. In some aspects, theadrenergic receptor modulator enhances an activity of an adrenergicreceptor by at least about or about any of 10%, 20%, 30%, 40%, 50%, 60%,70%, 80%, 90%, 95% or 100 or 200% or 300% or 400% or 500% or more ascompared to the corresponding activity in the same subject prior totreatment with the adrenergic receptor modulator or compared to thecorresponding activity in other subjects not receiving the adrenergicreceptor modulator. In some aspects, the adrenergic receptor modulatoris capable of binding to the active site of an adrenergic receptor(e.g., a binding site for a ligand). In some embodiments, the adrenergicreceptor modulator is capable of binding to an allosteric site of anadrenergic receptor.

As used herein, the term “dopamine receptor modulator” intends andencompasses a compound that binds to or inhibits binding of a ligand toa dopamine receptor or reduces or eliminates or increases or enhances ormimics an activity of a dopamine receptor. As such, a “dopamine receptormodulator” encompasses both a dopamine receptor antagonist and adopamine receptor agonist. In some aspects, the dopamine receptormodulator binds to or inhibits binding of a ligand to a dopamine-1 (D₁)and/or a dopamine-2 (D₂) receptor or reduces or eliminates or increasesor enhances or mimics an activity of a dopamine-1 (D₁) and/or adopamine-2 (D₂) receptor in a reversible or irreversible manner.Dopamine D₂ receptors are divided into two categories, D_(2L) andD_(2S), which are formed from a single gene by differential splicing.D_(2L) receptors have a longer intracellular domain than D_(2S). In someembodiments, the dopamine receptor modulator inhibits binding of aligand by at least about or about any one of 10%, 20%, 30%, 40%, 50%,60%, 70%, 80%, 90%, 95% or 100% as determined in the assays describedherein. In some embodiments, the dopamine receptor modulator reduces anactivity of a dopamine receptor by at least about or about any of 10%,20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as compared to thecorresponding activity in the same subject prior to treatment with thedopamine receptor modulator or compared to the corresponding activity inother subjects not receiving the dopamine receptor modulator. In someembodiments, the dopamine receptor modulator enhances an activity of adopamine receptor by at least about or about any of 10%, 20%, 30%, 40%,50%, 60%, 70%, 80%, 90%, 95% or 100 or 200% or 300% or 400% or 500% ormore as compared to the corresponding activity in the same subject priorto treatment with the dopamine receptor modulator or compared to thecorresponding activity in other subjects not receiving the dopaminereceptor modulator. In some embodiments, the dopamine receptor modulatoris capable of binding to the active site of a dopamine receptor (e.g., abinding site for a ligand). In some embodiments, the dopamine receptormodulator is capable of binding to an allosteric site of a dopaminereceptor.

As used herein, the term “serotonin receptor modulator” intends andencompasses a compound that binds to or inhibits binding of a ligand toa serotonin receptor or reduces or eliminates or increases or enhancesor mimics an activity of a serotonin receptor. As such, a “serotoninreceptor modulator” encompasses both a serotonin receptor antagonist anda serotonin receptor agonist. In some embodiments, the serotoninreceptor modulator binds to or inhibits binding of a ligand to a5-HT_(1A) and/or a 5-HT_(1B) and/or a 5-HT_(2A) and/or a 5-HT_(2B)and/or a 5-HT_(2C) and/or a 5-HT₃ and/or a 5-HT₄ and/or a 5-HT₆ and/or a5-HT₇ receptor or reduces or eliminates or increases or enhances ormimics an activity of a 5-HT_(1A) and/or a 5-HT_(1B) and/or a 5-HT_(2A)and/or a 5-HT_(2B) and/or a 5-HT_(2C) and/or a 5-HT₃ and/or a 5-HT₄and/or a 5-HT₆ and/or a 5-HT₇ receptor in a reversible or irreversiblemanner. In some embodiments, the serotonin receptor modulator inhibitsbinding of a ligand by at least about or about any one of 10%, 20%, 30%,40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as determined in the assaysdescribed herein. In some embodiments, the serotonin receptor modulatorreduces an activity of a serotonin receptor by at least about or aboutany of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% ascompared to the corresponding activity in the same subject prior totreatment with the serotonin receptor modulator or compared to thecorresponding activity in other subjects not receiving the serotoninreceptor modulator. In some embodiments, the serotonin receptormodulator enhances an activity of a serotonin receptor by at least aboutor about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100or 200% or 300% or 400% or 500% or more as compared to the correspondingactivity in the same subject prior to treatment with the serotoninreceptor modulator or compared to the corresponding activity in othersubjects not receiving the serotonin receptor modulator. In someembodiments, the serotonin receptor modulator is capable of binding tothe active site of a serotonin receptor (e.g., a binding site for aligand). In some embodiments, the serotonin receptor modulator iscapable of binding to an allosteric site of a serotonin receptor.

As used herein, the term “histamine receptor modulator” intends andencompasses a compound that reduces or eliminates or increases orenhances an activity of a histamine receptor. As such, a “histaminereceptor modulator” encompasses both a histamine receptor antagonist anda histamine receptor agonist. In some embodiments, the histaminereceptor modulator reduces or eliminates or increases or enhances anactivity of a histamine receptor in a reversible or irreversible manner.In some embodiments, the histamine receptor modulator reduces anactivity of a histamine receptor by at least or about any of 10%, 20%,30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as compared to thecorresponding activity in the same individual prior to treatment withthe histamine receptor modulator or compared to the correspondingactivity in like individuals not receiving the histamine receptormodulator. In some embodiments, the histamine receptor modulatorenhances an activity of a histamine receptor by at least or about any of10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100 or 200% or 300%or 400% or 500% or more as compared to the corresponding activity in thesame individual prior to treatment with the histamine receptor modulatoror compared to the corresponding activity in like individuals notreceiving the histamine receptor modulator. In some embodiments, thehistamine receptor modulator is capable of binding to the active site ofa histamine receptor (e.g., a binding site for a ligand). In someembodiments, the histamine receptor modulator is capable of binding toan allosteric site of a histamine receptor.

Unless clearly indicated otherwise, “an individual” as used hereinintends a mammal, including but not limited to a human. An individualincludes but is not limited to human, bovine, primate, equine, canine,feline, porcine, and ovine animals. Thus, the invention finds use inboth human medicine and in the veterinary context, including use inagricultural animals and domestic pets. The individual may be a humanwho has been diagnosed with or is suspected of having a cognitivedisorder, a psychotic disorder, a neurotransmitter-mediated disorderand/or a neuronal disorder. The individual may be a human who exhibitsone or more symptoms associated with a cognitive disorder, a psychoticdisorder, a neurotransmitter-mediated disorder and/or a neuronaldisorder. The individual may be a human who has a mutated or abnormalgene associated with a cognitive disorder, a psychotic disorder, aneurotransmitter-mediated disorder and/or a neuronal disorder. Theindividual may be a human who is genetically or otherwise predisposed todeveloping a cognitive disorder, a psychotic disorder, aneurotransmitter-mediated disorder and/or a neuronal disorder.

As used herein, “treatment” or “treating” is an approach for obtaining abeneficial or desired result, such as a clinical result.

For purposes of this invention, beneficial or desired clinical resultsinclude, but are not limited to, alleviation of a symptom and/ordiminishment of the extent of a symptom and/or preventing a worsening ofa symptom associated with a disease or condition. In one variation,beneficial or desired clinical results include, but are not limited to,alleviation of a symptom and/or diminishment of the extent of a symptomand/or preventing a worsening of a symptom associated with a cognitivedisorder, a psychotic disorder, a neurotransmitter-mediated disorderand/or a neuronal disorder. Preferably, treatment of a disease orcondition with a compound of the invention or a pharmaceuticallyacceptable salt thereof is accompanied by no or fewer side effects thanare associated with currently available therapies for the disease orcondition and/or improves the quality of life of the individual.

As used herein, “delaying” development of a disease or condition meansto defer, hinder, slow, retard, stabilize and/or postpone development ofthe disease or condition. This delay can be of varying lengths of time,depending on the history of the disease and/or individual being treated.As is evident to one skilled in the art, a sufficient or significantdelay can, in effect, encompass prevention, in that the individual doesnot develop the disease or condition. For example, a method that“delays” development of Alzheimer's disease is a method that reducesprobability of disease development in a given time frame and/or reducesextent of the disease in a given time frame, when compared to not usingthe method. Such comparisons are typically based on clinical studies,using a statistically significant number of subjects. For example,Alzheimer's disease development can be detected using standard clinicaltechniques, such as routine neurological examination, patient interview,neuroimaging, detecting alterations of levels of specific proteins inthe serum or cerebrospinal fluid (e.g., amyloid peptides and Tau),computerized tomography (CT) or magnetic resonance imaging (MRI).Similar techniques are known in the art for other diseases andconditions. Development may also refer to disease progression that maybe initially undetectable and includes occurrence, recurrence and onset.

As used herein, an “at risk” individual is an individual who is at riskof developing a cognitive disorder, a psychotic disorder, aneurotransmitter-mediated disorder and/or a neuronal disorder that canbe treated with a compound of the invention. An individual “at risk” mayor may not have a detectable disease or condition, and may or may nothave displayed detectable disease prior to the treatment methodsdescribed herein. “At risk” denotes that an individual has one or moreso-called risk factors, which are measurable parameters that correlatewith development of a disease or condition and are known in the art. Anindividual having one or more of these risk factors has a higherprobability of developing the disease or condition than an individualwithout these risk factor(s). These risk factors include, but are notlimited to, age, sex, race, diet, history of previous disease, presenceof precursor disease, genetic (i.e., hereditary) considerations, andenvironmental exposure. For example, individuals at risk for Alzheimer'sdisease include, e.g., those having relatives who have experienced thisdisease and those whose risk is determined by analysis of genetic orbiochemical markers. Genetic markers of risk for Alzheimer's diseaseinclude mutations in the APP gene, particularly mutations at position717 and positions 670 and 671 referred to as the Hardy and Swedishmutations, respectively (Hardy, Trends Neurosci., 20:154-9, 1997). Othermarkers of risk are mutations in the presenilin genes (e.g., PS1 orPS2), ApoE4 alleles, family history of Alzheimer's disease,hypercholesterolemia and/or atherosclerosis. Other such factors areknown in the art for other diseases and conditions.

As used herein, the term “pro-cognitive” includes but is not limited toan improvement of one or more mental processes such as memory,attention, perception and/or thinking, which may be assessed by methodsknown in the art.

As used herein, the term “neurotrophic” effects includes but is notlimited to effects that enhance neuron function such as growth, survivaland/or neurotransmitter synthesis.

As used herein, the term “cognitive disorders” refers to and intendsdiseases and conditions that are believed to involve or be associatedwith or do involve or are associated with progressive loss of structureand/or function of neurons, including death of neurons, and where acentral feature of the disorder may be the impairment of cognition(e.g., memory, attention, perception and/or thinking). These disordersinclude pathogen-induced cognitive dysfunction, e.g., HIV associatedcognitive dysfunction and Lyme disease associated cognitive dysfunction.Examples of cognitive disorders include Alzheimer's Disease,Huntington's Disease, Parkinson's Disease, schizophrenia, amyotrophiclateral sclerosis (ALS), autism, mild cognitive impairment (MCI),stroke, traumatic brain injury (TBI) and age-associated memoryimpairment (AAMI).

As used herein, the term “psychotic disorders” refers to and intendsmental diseases or conditions that are believed to cause or do causeabnormal thinking and perceptions. Psychotic disorders are characterizedby a loss of reality which may be accompanied by delusions,hallucinations (perceptions in a conscious and awake state in theabsence of external stimuli which have qualities of real perception, inthat they are vivid, substantial, and located in external objectivespace), personality changes and/or disorganized thinking. Other commonsymptoms include unusual or bizarre behavior, as well as difficulty withsocial interaction and impairment in carrying out the activities ofdaily living. Exemplary psychotic disorders are schizophrenia, bipolardisorders, psychosis, anxiety and depression.

As used herein, the term “neurotransmitter-mediated disorders” refers toand intends diseases or conditions that are believed to involve or beassociated with or do involve or are associated with abnormal levels ofneurotransmitters such as histamine, serotonin, dopamine, norepinephrineor impaired function of aminergic G protein-coupled receptors. Exemplaryneurotransmitter-mediated disorders include spinal cord injury, diabeticneuropathy, allergic diseases and diseases involving geroprotectiveactivity such as age-associated hair loss (alopecia), age-associatedweight loss and age-associated vision disturbances (cataracts). Abnormalneurotransmitter levels are associated with a wide variety of diseasesand conditions including, but not limited, to Alzheimer's disease,Parkinson's Disease, autism, Guillain-Barré syndrome, mild cognitiveimpairment, schizophrenia, anxiety, multiple sclerosis, stroke,traumatic brain injury, spinal cord injury, diabetic neuropathy,fibromyalgia, bipolar disorders, psychosis, depression and a variety ofallergic diseases.

As used herein, the term “neuronal disorders” refers to and intendsdiseases or conditions that are believed to involve, or be associatedwith, or do involve or are associated with neuronal cell death and/orimpaired neuronal function or decreased neuronal function. Exemplaryneuronal indications include neurodegenerative diseases and disorderssuch as Alzheimer's disease, Huntington's disease, amyotrophic lateralsclerosis (ALS), Parkinson's disease, canine cognitive dysfunctionsyndrome (CCDS), Lewy body disease, Menkes disease, Wilson disease,Creutzfeldt-Jakob disease, Fahr disease, an acute or chronic disorderinvolving cerebral circulation, such as ischemic or hemorrhagic strokeor other cerebral hemorrhagic insult, age-associated memory impairment(AAMI), mild cognitive impairment (MCI), injury-related mild cognitiveimpairment (MCI), post-concussion syndrome, post-traumatic stressdisorder, adjuvant chemotherapy, traumatic brain injury (TBI), neuronaldeath mediated ocular disorder, macular degeneration, age-relatedmacular degeneration, autism, including autism spectrum disorder,Asperger syndrome, and Rett syndrome, an avulsion injury, a spinal cordinjury, myasthenia gravis, Guillain-Barré syndrome, multiple sclerosis,diabetic neuropathy, fibromyalgia, neuropathy associated with spinalcord injury, schizophrenia, bipolar disorder, psychosis, anxiety ordepression.

As used herein, the term “neuron” represents a cell of ectodermalembryonic origin derived from any part of the nervous system of ananimal. Neurons express well-characterized neuron-specific markers,including neurofilament proteins, NeuN (Neuronal Nuclei marker), MAP2,and class III tubulin. Included as neurons are, for example,hippocampal, cortical, midbrain dopaminergic, spinal motor, sensory,sympathetic, septal cholinergic, and cerebellar neurons.

As used herein, the term “neurite outgrowth” or “neurite activation”refers to the extension of existing neuronal processes (e.g., axons anddendrites) and the growth or sprouting of new neuronal processes (e.g.,axons and dendrites). Neurite outgrowth or neurite activation may alterneural connectivity, resulting in the establishment of new synapses orthe remodeling of existing synapses.

As used herein, the term “neurogenesis” refers to the generation of newnerve cells from undifferentiated neuronal progenitor cells, also knownas multipotential neuronal stem cells. Neurogenesis actively producesnew neurons, astrocytes, glia, Schwann cells, oligodendrocytes and/orother neural lineages. Much neurogenesis occurs early in humandevelopment, though it continues later in life, particularly in certainlocalized regions of the adult brain.

As used herein, the term “neural connectivity” refers to the number,type, and quality of connections (“synapses”) between neurons in anorganism. Synapses form between neurons, between neurons and muscles (a“neuromuscular junction”), and between neurons and other biologicalstructures, including internal organs, endocrine glands, and the like.Synapses are specialized structures by which neurons transmit chemicalor electrical signals to each other and to non-neuronal cells, muscles,tissues, and organs. Compounds that affect neural connectivity may do soby establishing new synapses (e.g., by neurite outgrowth or neuriteactivation) or by altering or remodeling existing synapses. Synapticremodeling refers to changes in the quality, intensity or type of signaltransmitted at particular synapses.

As used herein, the term “neuropathy” refers to a disorder characterizedby altered function and/or structure of motor, sensory, and autonomicneurons of the nervous system, initiated or caused by a primary lesionor other dysfunction of the nervous system. Patterns of peripheralneuropathy include polyneuropathy, mononeuropathy, mononeuritismultiplex and autonomic neuropathy. The most common form is(symmetrical) peripheral polyneuropathy, which mainly affects the feetand legs. A radiculopathy involves spinal nerve roots, but if peripheralnerves are also involved the term radiculoneuropathy is used. The formof neuropathy may be further broken down by cause, or the size ofpredominant fiber involvement, e.g., large fiber or small fiberperipheral neuropathy. Central neuropathic pain can occur in spinal cordinjury, multiple sclerosis, and some strokes, as well as fibromyalgia.Neuropathy may be associated with varying combinations of weakness,autonomic changes and sensory changes. Loss of muscle bulk orfasciculations, a particular fine twitching of muscle may also be seen.Sensory symptoms encompass loss of sensation and “positive” phenomenaincluding pain. Neuropathies are associated with a variety of disorders,including diabetes (e.g., diabetic neuropathy), fibromyalgia, multiplesclerosis, and herpes zoster infection, as well as with spinal cordinjury and other types of nerve damage.

As used herein, the term “Alzheimer's disease” refers to a degenerativebrain disorder characterized clinically by progressive memory deficits,confusion, behavioral problems, inability to care for oneself, gradualphysical deterioration and, ultimately, death. Histologically, thedisease is characterized by neuritic plaques, found primarily in theassociation cortex, limbic system and basal ganglia. The majorconstituent of these plaques is amyloid beta peptide (Aβ), which is thecleavage product of beta amyloid precursor protein (βAPP or APP). APP isa type I transmembrane glycoprotein that contains a large ectopicN-terminal domain, a transmembrane domain and a small cytoplasmicC-terminal tail. Alternative splicing of the transcript of the singleAPP gene on chromosome 21 results in several isoforms that differ in thenumber of amino acids. Aβ appears to have a central role in theneuropathology of Alzheimer's disease. Familial forms of the diseasehave been linked to mutations in APP and the presenilin genes (Tanzi etal., 1996, Neurobiol. Dis., 3:159-168; Hardy, 1996, Ann. Med.,28:255-258). Diseased-linked mutations in these genes result inincreased production of the 42-amino acid form of Aβ, the predominantform found in amyloid plaques. Mitochondrial dysfunction has also beenreported to be an important component of Alzheimer's disease (Bubber etal., Mitochondrial abnormalities in Alzheimer brain: MechanisticImplications, Ann Neurol., 2005, 57(5), 695-703; Wang et al., “Insightsinto amyloid-β-induced mitochondrial dysfunction in Alzheimer disease,”Free Radical Biology & Medicine, 2007, 43, 1569-1573; Swerdlow et al.,“Mitochondria in Alzheimer's disease,” Int. Rev. Neurobiol. 2002, 53,341-385; and Reddy et al., “Are mitochondria critical in thepathogenesis of Alzheimer's disease?,” Brain Res Rev. 2005, 49(3),618-32). It has been proposed that mitochondrial dysfunction has acausal relationship with neuronal function (including neurotransmittersynthesis and secretion) and viability. Compounds which stabilizemitochondria may therefore have a beneficial impact on Alzheimer'spatients.

As used herein, the term “Huntington's disease” refers to a fatalneurological disorder characterized clinically by symptoms such asinvoluntary movements, cognition impairment or loss of cognitivefunction and a wide spectrum of behavioral disorders. Common motorsymptoms associated with Huntington's disease include chorea(involuntary writhing and spasming), clumsiness, and progressive loss ofthe abilities to walk, speak (e.g., exhibiting slurred speech) andswallow. Other symptoms of Huntington's disease can include cognitivesymptoms such as loss of intellectual speed, attention and short-termmemory and/or behavioral symptoms that can span the range of changes inpersonality, depression, irritability, emotional outbursts and apathy.Clinical symptoms typically appear in the fourth or fifth decade oflife. Huntington's disease is a devastating and often protractedillness, with death usually occurring approximately 10-20 years afterthe onset of symptoms. Huntington's disease is inherited through amutated or abnormal gene encoding an abnormal protein called the mutanthuntingtin protein; the mutated huntingtin protein produces neuronaldegeneration in many different regions of the brain. The degenerationfocuses on neurons located in the basal ganglia, structures deep withinthe brain that control many important functions including coordinatingmovement, and on neurons on the outer surface of the brain or cortex,which controls thought, perception and memory.

“Amyotrophic lateral sclerosis” or “ALS” is used herein to denote aprogressive neurodegenerative disease that affects upper motor neurons(motor neurons in the brain) and/or lower motor neurons (motor neuronsin the spinal cord) and results in motor neuron death. As used herein,the term “ALS” includes all of the classifications of ALS known in theart, including, but not limited to classical ALS (typically affectingboth lower and upper motor neurons), Primary Lateral Sclerosis (PLS,typically affecting only the upper motor neurons), Progressive BulbarPalsy (PBP or Bulbar Onset, a version of ALS that typically begins withdifficulties swallowing, chewing and speaking), Progressive MuscularAtrophy (PMA, typically affecting only the lower motor neurons) andfamilial ALS (a genetic version of ALS).

The term “Parkinson's disease” as used herein refers to any medicalcondition wherein an individual experiences one or more symptomsassociated with Parkinson's disease, such as without limitation one ormore of the following symptoms: rest tremor, cogwheel rigidity,bradykinesia, postural reflex impairment, symptoms having good responseto 1-dopa treatment, the absence of prominent oculomotor palsy,cerebellar or pyramidal signs, amyotrophy, dyspraxia and/or dysphasia.In a specific embodiment, the present invention is utilized for thetreatment of a dopaminergic dysfunction-related disorder. In a specificembodiment, the individual with Parkinson's disease has a mutation orpolymorphism in a synuclein, parkin or NURR1 nucleic acid that isassociated with Parkinson's disease. In one embodiment, the individualwith Parkinson's disease has defective or decreased expression of anucleic acid or a mutation in a nucleic acid that regulates thedevelopment and/or survival of dopaminergic neurons.

As used herein, the term “canine cognitive dysfunction syndrome,” or“CCDS” refers to an age-related deterioration of mental functiontypified by multiple cognitive impairments that affect an afflictedcanine's ability to function normally. The decline in cognitive abilitythat is associated with CCDS cannot be completely attributed to ageneral medical condition such as neoplasia, infection, sensoryimpairment, or organ failure. Diagnosis of CCDS in canines, such asdogs, is generally a diagnosis of exclusion, based on thorough behaviorand medical histories and the presence of clinical symptoms of CCDS thatare unrelated to other disease processes. Owner observation ofage-related changes in behavior is a practical means used to detect thepossible onset of CCDS in aging domestic dogs. A number of laboratorycognitive tasks may be used to help diagnose CCDS, while blood counts,chemistry panels and urinalysis can be used to rule out other underlyingdiseases that could mimic the clinical symptoms of CCDS. Symptoms ofCCDS include memory loss, which in domestic dogs may be manifested bydisorientation and/or confusion, decreased or altered interaction withfamily members and/or greeting behavior, changes in sleep-wake cycle,decreased activity level, and loss of house training or frequent,inappropriate elimination. A canine suffering from CCDS may exhibit oneor more of the following clinical or behavioral symptoms: decreasedappetite, decreased awareness of surroundings, decreased ability torecognize familiar places, people or other animals, decreased hearing,decreased ability to climb up and down stairs, decreased tolerance tobeing alone, development of compulsive behavior or repetitive behaviorsor habits, circling, tremors or shaking, disorientation, decreasedactivity level, abnormal sleep wake cycles, loss of house training,decreased or altered responsiveness to family members, and decreased oraltered greeting behavior. CCDS can dramatically affect the health andwell-being of an afflicted canine. Moreover, the companionship offeredby a pet with CCDS can become less rewarding as the severity of thedisease increases and its symptoms become more severe.

As used herein, the term “age-associated memory impairment” or “AAMI”refers to a condition that may be identified as GDS stage 2 on theglobal deterioration scale (GDS) (Reisberg, et al. (1982) Am. J.Psychiatry 139: 1136-1139) which differentiates the aging process andprogressive degenerative dementia in seven major stages. The first stageof the GDS is one in which individuals at any age have neithersubjective complaints of cognitive impairment nor objective evidence ofimpairment. These GDS stage 1 individuals are considered normal. Thesecond stage of the GDS applies to those generally elderly persons whocomplain of memory and cognitive functioning difficulties such as notrecalling names as well as they could five or ten years previously ornot recalling where they have placed things as well as they could fiveor ten years previously. These subjective complaints appear to be verycommon in otherwise normal elderly individuals. AAMI refers to personsin GDS stage 2, who may differ neurophysiologically from elderly personswho are normal and free of subjective complaints, e.g., GDS stage 1. Forexample, AAMI subjects have been found to have more electrophysiologicslowing on a computer analyzed EEG than GDS stage 1 elderly persons(Prichep, John, Ferris, Reisberg, et al. (1994) Neurobiol. Aging 15:85-90).

As used herein, the term “mild cognitive impairment” or “MCI” refers toa type of cognitive disorder characterized by a more pronounceddeterioration in cognitive functions than is typical for normalage-related decline. As a result, elderly or aged patients with MCI havegreater than normal difficulty performing complex daily tasks andlearning, but without the inability to perform normal social, everyday,and/or professional functions typical of patients with Alzheimer'sdisease, or other similar neurodegenerative disorders eventuallyresulting in dementia. MCI is characterized by subtle, clinicallymanifest deficits in cognition, memory, and functioning, amongst otherimpairments, which are not of sufficient magnitude to fulfill criteriafor diagnosis of Alzheimer's disease or other dementia. MCI alsoencompasses injury-related MCI, defined herein as cognitive impairmentresulting from certain types of injury, such as nerve injury (e.g.,battlefield injuries, including post-concussion syndrome, and the like),neurotoxic treatment (e.g., adjuvant chemotherapy resulting in “chemobrain” and the like), and tissue damage resulting from physical injuryor other neurodegeneration, which is separate and distinct from mildcognitive impairment resulting from stroke, ischemia, hemorrhagicinsult, blunt force trauma, and the like.

As used herein, the term “traumatic brain injury” or “TBI” refers to abrain injury caused by a sudden trauma, such as a blow or jolt or apenetrating head injury, which disrupts the function or damages thebrain. Symptoms of TBI can range from mild, moderate to severe and cansignificantly affect many cognitive (deficits of language andcommunication, information processing, memory, and perceptual skills),physical (ambulation, balance, coordination, fine motor skills,strength, and endurance), and psychological skills

“Neuronal death mediated ocular disease” intends an ocular disease inwhich death of the neuron is implicated in whole or in part. The diseasemay involve death of photoreceptors. The disease may involve retinalcell death. The disease may involve ocular nerve death by apoptosis.Particular neuronal death mediated ocular diseases include but are notlimited to macular degeneration, glaucoma, retinitis pigmentosa,congenital stationary night blindness (Oguchi disease), childhood onsetsevere retinal dystrophy, Leber congenital amaurosis, Bardet-Biedlesyndrome, Usher syndrome, blindness from an optic neuropathy, Leber'shereditary optic neuropathy, color blindness and Hansen-Larson-Bergsyndrome.

As used herein, the term “macular degeneration” includes all forms andclassifications of macular degeneration known in the art, including, butnot limited to diseases that are characterized by a progressive loss ofcentral vision associated with abnormalities of Bruch's membrane, thechoroid, the neural retina and/or the retinal pigment epithelium. Theterm thus encompasses disorders such as age-related macular degeneration(ARMD) as well as rarer, earlier-onset dystrophies that in some casescan be detected in the first decade of life. Other maculopathies includeNorth Carolina macular dystrophy, Sorsby's fundus dystrophy, Stargardt'sdisease, pattern dystrophy, Best disease, and Malattia Leventinese.

As used herein, the term “autism” refers to a brain development disorderthat impairs social interaction and communication and causes restrictedand repetitive behavior, typically appearing during infancy or earlychildhood. The cognitive and behavioral defects are thought to result inpart from altered neural connectivity. Autism encompasses relateddisorders sometimes referred to as “autism spectrum disorder,” as wellas Asperger syndrome and Rett syndrome.

As used herein, the term “nerve injury” or “nerve damage” refers tophysical damage to nerves, such as avulsion injury (e.g., where a nerveor nerves have been torn or ripped) or spinal cord injury (e.g., damageto white matter or myelinated fiber tracts that carry sensation andmotor signals to and from the brain). Spinal cord injury can occur frommany causes, including physical trauma (e.g., car accidents, sportsinjuries, and the like), tumors impinging on the spinal column,developmental disorders, such as spina bifida, and the like.

As used herein, the term “myasthenia gravis” or “MG” refers to anon-cognitive neuromuscular disorder caused by immune-mediated loss ofacetylcholine receptors at neuromuscular junctions of skeletal muscle.Clinically, MG typically appears first as occasional muscle weakness inapproximately two-thirds of patients, most commonly in the extraocularmuscles. These initial symptoms eventually worsen, producing droopingeyelids (ptosis) and/or double vision (diplopia), often causing thepatient to seek medical attention. Eventually, many patients developgeneral muscular weakness that may fluctuate weekly, daily, or even morefrequently. Generalized MG often affects muscles that control facialexpression, chewing, talking, swallowing, and breathing; before recentadvances in treatment, respiratory failure was the most common cause ofdeath.

As used herein, the term “Guillain-Barré syndrome” refers to anon-cognitive disorder in which the body's immune system attacks part ofthe peripheral nervous system. The first symptoms of this disorderinclude varying degrees of weakness or tingling sensations in the legs.In many instances the weakness and abnormal sensations spread to thearms and upper body. These symptoms can increase in intensity untilcertain muscles cannot be used at all and, when severe, the patient isalmost totally paralyzed. In these cases the disorder is lifethreatening—potentially interfering with breathing and, at times, withblood pressure or heart rate—and is considered a medical emergency. Mostpatients, however, recover from even the most severe cases ofGuillain-Barré syndrome, although some continue to have a certain degreeof weakness.

As used herein, the term “multiple sclerosis” or “MS” refers to anautoimmune condition in which the immune system attacks the centralnervous system (CNS), leading to demyelination of neurons. It may causenumerous symptoms, many of which are non-cognitive, and often progressesto physical disability. MS affects the areas of the brain and spinalcord known as the white matter. White matter cells carry signals betweenthe grey matter areas, where the processing is done, and the rest of thebody. More specifically, MS destroys oligodendrocytes which are thecells responsible for creating and maintaining a fatty layer, known asthe myelin sheath, which helps the neurons carry electrical signals. MSresults in a thinning or complete loss of myelin and, less frequently,the cutting (transection) of the neuron's extensions or axons. When themyelin is lost, the neurons can no longer effectively conduct theirelectrical signals. Almost any neurological symptom can accompany thedisease. MS takes several forms, with new symptoms occurring either indiscrete attacks (relapsing forms) or slowly accumulating over time(progressive forms). Most people are first diagnosed withrelapsing-remitting MS but develop secondary-progressive MS (SPMS) aftera number of years. Between attacks, symptoms may go away completely, butpermanent neurological problems often persist, especially as the diseaseadvances.

As used herein, the term “schizophrenia” refers to a chronic, mentaldisorder characterized by one or more positive symptoms (e.g., delusionsand hallucinations) and/or negative symptoms (e.g., blunted emotions andlack of interest) and/or disorganized symptoms (e.g., disorganizedthinking and speech or disorganized perception and behavior).Schizophrenia as used herein includes all forms and classifications ofschizophrenia known in the art, including, but not limited to catatonictype, hebephrenic type, disorganized type, paranoid type, residual typeor undifferentiated type schizophrenia and deficit syndrome and/or thosedescribed in American Psychiatric Association: Diagnostic andStatistical Manual of Mental Disorders, Fourth Edition, Washington D.C.,2000 or in International Statistical Classification of Diseases andRelated Health Problems, or otherwise known to those of skill in theart.

As used herein, “Cognitive impairment associated with schizophrenia” or“CIAS” includes neuropsychological deficits in attention, workingmemory, verbal learning, and problem solving. These deficits arebelieved to be linked to impairment in functional status (e.g., socialbehavior, work performance, and activities of daily living).

As used herein “geroprotective activity” or “geroprotector” means abiological activity that slows down ageing and/or prolongs life and/orincreases or improves the quality of life via a decrease in the amountand/or the level of intensity of pathologies or conditions that are notlife-threatening but are associated with the aging process and which aretypical for elderly people. Pathologies or conditions that are notlife-threatening but are associated with the aging process include suchpathologies or conditions as loss of sight (cataract), deterioration ofthe dermatohairy integument (alopecia), and an age-associated decreasein weight due to the death of muscular and/or fatty cells.

As used herein, attention-deficit hyperactivity disorder (ADHD) is themost common child neuropsychiatric condition present in school-agedchildren, affecting about 5-8% of this population. ADHD refers to achronic disorder that initially manifests in childhood and ischaracterized by hyperactivity, impulsivity, and/or inattention. ADHD ischaracterized by persistent patterns of inattention and/orimpulsivity-hyperactivity that are much more extreme than is observed inindividuals at the same developmental level or stage. There isconsiderable evidence, from family and twin studies, that ADHD has asignificant genetic component. This disorder is thought to be due to aninteraction of environmental and genetic factors. ADHD includes allknown types of ADHD. For example, Diagnostic & Statistical Manual forMental Disorders (DSM-IV) identifies three subtypes of ADHD: (1) ADHD,Combined Type which is characterized by both inattention andhyperactivity-impulsivity symptoms; (2) ADHD, Predominantly InattentiveType which is characterized by inattention but nothyperactivity-impulsivity symptoms; and (3) ADHD, PredominantlyHyperactive-Impulsive Type which is characterized byHyperactivity-impulsivity but not inattention symptoms.

As used herein, attention-deficit disorder (ADD) refers to a disorder inprocessing neural stimuli that is characterized by distractibility andimpulsivity that can result in inability to control behavior and canimpair an individual's social, academic, or occupational function anddevelopment. ADD may be diagnosed by known methods, which may includeobserving behavior and diagnostic interview techniques.

As used herein “allergic disease” refers to a disorder of the immunesystem which is characterized by excessive activation of mast cells andbasophils and production of IgE immunoglobulins, resulting in an extremeinflammatory response. It represents a form of hypersensitivity to anenvironmental substance known as allergen and is an acquired disease.Common allergic reactions include eczema, hives, hay fever, asthma, foodallergies, and reactions to the venom of stinging insects such as waspsand bees. Allergic reactions are accompanied by an excessive release ofhistamines, and can thus be treated with antihistaminic agents.

As used herein, by “combination therapy” is meant a therapy thatincludes two or more different compounds. Thus, in one aspect, acombination therapy comprising a compound detailed herein and anthercompound is provided. In some variations, the combination therapyoptionally includes one or more pharmaceutically acceptable carriers orexcipients, non-pharmaceutically active compounds, and/or inertsubstances. In various embodiments, treatment with a combination therapymay result in an additive or even synergistic (e.g., greater thanadditive) result compared to administration of a single compound of theinvention alone. In some embodiments, a lower amount of each compound isused as part of a combination therapy compared to the amount generallyused for individual therapy. Preferably, the same or greater therapeuticbenefit is achieved using a combination therapy than by using any of theindividual compounds alone. In some embodiments, the same or greatertherapeutic benefit is achieved using a smaller amount (e.g., a lowerdose or a less frequent dosing schedule) of a compound in a combinationtherapy than the amount generally used for individual compound ortherapy. Preferably, the use of a small amount of compound results in areduction in the number, severity, frequency, and/or duration of one ormore side-effects associated with the compound.

As used herein, the term “effective amount” intends such amount of acompound of the invention which in combination with its parameters ofefficacy and toxicity, as well as based on the knowledge of thepracticing specialist should be effective in a given therapeutic form.As is understood in the art, an effective amount may be in one or moredoses, e.g., a single dose or multiple doses may be required to achievethe desired treatment endpoint. An effective amount may be considered inthe context of administering one or more therapeutic agents, and asingle agent may be considered to be given in an effective amount if, inconjunction with one or more other agents, a desirable or beneficialresult may be or is achieved. Suitable doses of any of theco-administered compounds may optionally be lowered due to the combinedaction (e.g., additive or synergistic effects) of the compounds.

As used herein, “unit dosage form” refers to physically discrete units,suitable as unit dosages, each unit containing a predetermined quantityof active ingredient calculated to produce the desired therapeuticeffect in association with the required pharmaceutical carrier. Unitdosage forms may contain a single or a combination therapy.

As used herein, the term “controlled release” refers to adrug-containing formulation or fraction thereof in which release of thedrug is not immediate, e.g., with a “controlled release” formulation,administration does not result in immediate release of the drug into anabsorption pool. The term encompasses depot formulations designed togradually release the drug compound over an extended period of time.Controlled release formulations can include a wide variety of drugdelivery systems, generally involving mixing the drug compound withcarriers, polymers or other compounds having the desired releasecharacteristics (e.g., pH-dependent or non-pH-dependent solubility,different degrees of water solubility, and the like) and formulating themixture according to the desired route of delivery (e.g., coatedcapsules, implantable reservoirs, injectable solutions containingbiodegradable capsules, and the like).

As used herein, by “pharmaceutically acceptable” or “pharmacologicallyacceptable” is meant a material that is not biologically or otherwiseundesirable, e.g., the material may be incorporated into apharmaceutical composition administered to a patient without causing anysignificant undesirable biological effects or interacting in adeleterious manner with any of the other components of the compositionin which it is contained. Pharmaceutically acceptable carriers orexcipients have preferably met the required standards of toxicologicaland manufacturing testing and/or are included on the Inactive IngredientGuide prepared by the U.S. Food and Drug administration.

“Pharmaceutically acceptable salts” are those salts which retain atleast some of the biological activity of the free (non-salt) compoundand which can be administered as drugs or pharmaceuticals to anindividual. Such salts, for example, include: (1) acid addition salts,formed with inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like; or formedwith organic acids such as acetic acid, oxalic acid, propionic acid,succinic acid, maleic acid, tartaric acid and the like; (2) salts formedwhen an acidic proton present in the parent compound either is replacedby a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or analuminum ion; or coordinates with an organic base. Acceptable organicbases include ethanolamine, diethanolamine, triethanolamine and thelike. Acceptable inorganic bases include aluminum hydroxide, calciumhydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, andthe like. Pharmaceutically acceptable salts can be prepared in situ inthe manufacturing process, or by separately reacting a purified compoundof the invention in its free acid or base form with a suitable organicor inorganic base or acid, respectively, and isolating the salt thusformed during subsequent purification. It should be understood that areference to a pharmaceutically acceptable salt includes the solventaddition forms or crystal forms thereof, particularly solvates orpolymorphs. Solvates contain either stoichiometric or non-stoichiometricamounts of a solvent, and are often formed during the process ofcrystallization. Hydrates are formed when the solvent is water, oralcoholates are formed when the solvent is alcohol. Polymorphs includethe different crystal packing arrangements of the same elementalcomposition of a compound. Polymorphs usually have different X-raydiffraction patterns, infrared spectra, melting points, density,hardness, crystal shape, optical and electrical properties, stability,and solubility. Various factors such as the recrystallization solvent,rate of crystallization, and storage temperature may cause a singlecrystal form to dominate.

The term “excipient” as used herein means an inert or inactive substancethat may be used in the production of a drug or pharmaceutical, such asa tablet containing a compound of the invention as an active ingredient.Various substances may be embraced by the term excipient, includingwithout limitation any substance used as a binder, disintegrant,coating, compression/encapsulation aid, cream or lotion, lubricant,solutions for parenteral administration, materials for chewable tablets,sweetener or flavoring, suspending/gelling agent, or wet granulationagent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.;coatings include, e.g., cellulose acetate phthalate, ethylcellulose,gellan gum, maltodextrin, enteric coatings, etc.;compression/encapsulation aids include, e.g., calcium carbonate,dextrose, fructose dc (dc=“directly compressible”), honey dc, lactose(anhydrate or monohydrate; optionally in combination with aspartame,cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.;disintegrants include, e.g., croscarmellose sodium, gellan gum, sodiumstarch glycolate, etc.; creams or lotions include, e.g., maltodextrin,carrageenans, etc.; lubricants include, e.g., magnesium stearate,stearic acid, sodium stearyl fumarate, etc.; materials for chewabletablets include, e.g., dextrose, fructose dc, lactose (monohydrate,optionally in combination with aspartame or cellulose), etc.;suspending/gelling agents include, e.g., carrageenan, sodium starchglycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame,dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulationagents include, e.g., calcium carbonate, maltodextrin, microcrystallinecellulose, etc.

“Alkyl” refers to and includes saturated linear, branched, or cyclicunivalent hydrocarbon structures and combinations thereof. Particularalkyl groups are those having 1 to 20 carbon atoms (a “C₁-C₂₀ alkyl”).More particular alkyl groups are those having 1 to 8 carbon atoms (a“C₁-C₈ alkyl”). When an alkyl residue having a specific number ofcarbons is named, all geometric isomers having that number of carbonsare intended to be encompassed and described; thus, for example, “butyl”is meant to include n-butyl, sec-butyl, iso-butyl, tert-butyl andcyclobutyl; “propyl” includes n-propyl, iso-propyl and cyclopropyl. Thisterm is exemplified by groups such as methyl, t-butyl, n-heptyl, octyl,cyclohexylmethyl, cyclopropyl and the like. Cycloalkyl is a subset ofalkyl and can consist of one ring, such as cyclohexyl, or multiplerings, such as adamantyl. A cycloalkyl comprising more than one ring maybe fused, spiro or bridged, or combinations thereof. A preferredcycloalkyl is a saturated cyclic hydrocarbon having from 3 to 13 annularcarbon atoms. A more preferred cycloalkyl is a saturated cyclichydrocarbon having from 3 to 8 annular carbon atoms (a “C₃-C₈cycloalkyl”). Examples of cycloalkyl groups include adamantyl,decahydronaphthalenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyland the like.

“Alkylene” refers to the same residues as alkyl, but having bivalency.Examples of alkylene include methylene (—CH₂—), ethylene (—CH₂CH₂—),propylene (—CH₂CH₂CH₂—), butylene (—CH₂CH₂CH₂CH₂—) and the like.

“Alkenyl” refers to an unsaturated hydrocarbon group having at least onesite of olefinic unsaturation (i.e., having at least one moiety of theformula C═C) and preferably having from 2 to 10 carbon atoms and morepreferably 2 to 8 carbon atoms. Examples of alkenyl include but are notlimited to —CH₂—CH═CH—CH₃ and —CH₂—CH₂-cyclohexenyl, where the ethylgroup of the latter example can be attached to the cyclohexenyl moietyat any available position on the ring.

Cycloalkenyl is a subset of alkenyl and can consist of one ring, such ascyclohexyl, or multiple rings, such as norbornenyl. A more preferredcycloalkenyl is an unsaturated cyclic hydrocarbon having from 3 to 8annular carbon atoms (a “C₃-C₈ cycloalkenyl”). Examples of cycloalkenylgroups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyland the like.

“Alkynyl” refers to an unsaturated hydrocarbon group having at least onesite of acetylenic unsaturation (i.e., having at least one moiety of theformula C═C) and preferably having from 2 to 10 carbon atoms and morepreferably 3 to 8 carbon atoms. Alkynyl groups having 2 to 8 carbonatoms, and the like, is embraced.

Substituted alkyl” refers to an alkyl group having from 1 to 5substituents including, but not limited to, substituents such as alkoxy,substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino,substituted or unsubstituted amino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro,carboxyl, thiol, thioalkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl,sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Substituted alkenyl” refers to alkenyl group having from 1 to 5substituents s including, but not limited to, substituents such asalkoxy, substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino,substituted or unsubstituted amino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro,carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl,sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Substituted alkynyl” refers to alkynyl groups having from 1 to 5substituents including, but not limited to, groups such as alkoxy,substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino,substituted or unsubstituted amino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro,carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl,sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Acyl” refers to the groups H—C(O)—, alkyl-C(O)—, substitutedalkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—,substituted alkynyl-C(O)—, aryl-C(O)—, substituted aryl-C(O)—,heteroaryl-C(O)—, substituted heteroaryl-C(O)—, heterocyclic-C(O)—, andsubstituted heterocyclic-C(O)—, wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Acyloxy” refers to the groups H—C(O)O—, alkyl-C(O)O—, substitutedalkyl-C(O)O—, alkenyl-C(O)O—, substituted alkenyl-C(O)O—,alkynyl-C(O)O—, substituted alkynyl-C(O)O—, aryl-C(O)O—, substitutedaryl-C(O)O—, heteroaryl-C(O)O—, substituted heteroaryl-C(O)O—,heterocyclic-C(O)O—, and substituted heterocyclic-C(O)O—, wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocyclic are as defined herein.

In one variation, acyloxy is a cycloalkyl-C(O)O—, substitutedcycloalkyl-C(O)O— moiety.

“Heterocycle”, “heterocyclic”, or “heterocyclyl” refers to a saturatedor an unsaturated non-aromatic group having a single ring or multiplecondensed rings, and having from 1 to 10 annular carbon atoms and from 1to 4 annular heteroatoms, such as nitrogen, sulfur or oxygen, and thelike. A heterocycle comprising more than one ring may be fused, spiro orbridged, or any combination thereof. In fused ring systems, one or moreof the rings can be aryl or heteroaryl. A heterocycle having more thanone ring where at least one ring is aromatic may be connected to theparent structure at either a non-aromatic ring position or at anaromatic ring position. In one variation, a heterocycle having more thanone ring where at least one ring is aromatic is connected to the parentstructure at a non-aromatic ring position.

“Substituted heterocyclic” or “substituted heterocyclyl” refers to aheterocycle group which is substituted with from 1 to 3 substituentsincluding, but not limited to, substituents such as alkoxy, substitutedalkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted orunsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy,substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol,thioalkyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo,carbonylalkylenealkoxy and the like. In one variation, a substitutedheterocycle is a heterocycle substituted with an additional ring,wherein the additional ring may be aromatic or non-aromatic.

“Aryl” or “Ar” refers to an unsaturated aromatic carbocyclic grouphaving a single ring (e.g., phenyl) or multiple condensed rings (e.g.,naphthyl or anthryl) which condensed rings may or may not be aromatic.In one variation, the aryl group contains from 6 to 14 annular carbonatoms. An aryl group having more than one ring where at least one ringis non-aromatic may be connected to the parent structure at either anaromatic ring position or at a non-aromatic ring position. In onevariation, an aryl group having more than one ring where at least onering is non-aromatic is connected to the parent structure at an aromaticring position.

“Heteroaryl” or “HetAr” refers to an unsaturated aromatic carbocyclicgroup having from 2 to 10 annular carbon atoms and at least one annularheteroatom, including but not limited to heteroatoms such as nitrogen,oxygen and sulfur. A heteroaryl group may have a single ring (e.g.,pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl,benzothienyl) which condensed rings may or may not be aromatic. Aheteroaryl group having more than one ring where at least one ring isnon-aromatic may be connected to the parent structure at either anaromatic ring position or at a non-aromatic ring position. In onevariation, a heteroaryl group having more than one ring where at leastone ring is non-aromatic is connected to the parent structure at anaromatic ring position.

“Substituted aryl” refers to an aryl group having 1 to 5 substituentsincluding, but not limited to, groups such as alkoxy, substitutedalkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted orunsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, cyano,halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino,sulfonyl, oxo, carbonylalkylenealkoxy and the like.

In one variation, a substituted aryl comprises an aryl group substitutedby an aryl and/or substituted aryl substituent.

“Substituted heteroaryl” refers to a heteroaryl group having 1 to 5substituents including, but not limited to, groups such as alkoxy,substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino,substituted or unsubstituted amino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro,carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo,carbonylalkylenealkoxy and the like.

In one variation, a substituted heteroaryl comprises a heteroaryl groupsubstituted by a heteroaryl and/or substituted heteroaryl substituent.

“Aralkyl” refers to a residue in which an aryl moiety is attached to analkyl residue and wherein the aralkyl group may be attached to theparent structure at either the aryl or the alkyl residue. Preferably, anaralkyl is connected to the parent structure via the alkyl moiety. A“substituted aralkyl” refers to a residue in which an aryl moiety isattached to a substituted alkyl residue and wherein the aralkyl groupmay be attached to the parent structure at either the aryl or the alkylresidue.

When an aralkyl is connected to the parent structure via the alkylmoiety, it may also be referred to as an “alkaryl”. More particularalkaryl groups are those having 1 to 3 carbon atoms in the alkyl moiety(a “C₁-C₃ alkaryl”).

In one variation, an aralkyl is a fused ring system where at least onecycloalkyl moiety is fused with at least one aryl moiety.

“Alkoxy” refers to the group alkyl-O—, which includes, by way ofexample, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.Similarly, alkenyloxy refers to the group “alkenyl-O—” and alkynyloxyrefers to the group “alkynyl-O—”. “Substituted alkoxy” refers to thegroup substituted alkyl-O.

“Unsubstituted amino” refers to the group —NH₂.

“Substituted amino” refers to the group —NR_(a)R_(b), where either (a)each R_(a) and R_(b) group is independently selected from the groupconsisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, substituted heterocyclic, providedthat both R_(a) and R_(b) groups are not H; or (b) R_(a) and R_(b) arejoined together with the nitrogen atom to form a heterocyclic orsubstituted heterocyclic ring.

“Acylamino” refers to the group —C(O)NR_(a)R_(b) where R_(a) and R_(b)are independently selected from the group consisting of H, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic or R_(a) and R_(b) groups can bejoined together with the nitrogen atom to form a heterocyclic orsubstituted heterocyclic ring.

“Aminocarbonylalkoxy” refers to the group —NR_(a)C(O)OR_(b) where eachR_(a) and R_(b) group is independently selected from the groupconsisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclyl.

“Aminoacyl” refers to the group —NR_(a)C(O)R_(b) where each R_(a) andR_(b) group is independently selected from the group consisting of H,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic or substituted heterocyclic. Preferably, R_(a)is H or alkyl.

“Aminosulfonyl” refers to the groups —NRSO₂-alkyl, —NRSO₂ substitutedalkyl, —NRSO₂-alkenyl, —NRSO₂-substituted alkenyl, —NRSO₂-alkynyl,—NRSO₂-substituted alkynyl, —NRSO₂-aryl, —NRSO₂-substituted aryl,—NRSO₂-heteroaryl, —NRSO₂-substituted heteroaryl, —NRSO₂-heterocyclic,and —NRSO₂-substituted heterocyclic, where R is H or alkyl and whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

In one variation, an aminosulonyl is —NRSO₂-cycloalkyl or—NRSO₂-substituted cycloalkyl.

“Sulfonylamino” refers to the groups —SO₂NH₂, —SO₂NR-alkyl,—SO₂NR-substituted alkyl, —SO₂NR-alkenyl, —SO₂NR-substituted alkenyl,—SO₂NR-alkynyl, —SO₂NR-substituted alkynyl, —SO₂NR-aryl,—SO₂NR-substituted aryl, —SO₂NR-heteroaryl, —SO₂NR-substitutedheteroaryl, —SO₂NR-heterocyclic, and —SO₂NR-substituted heterocyclic,where R is H or alkyl, or —SO₂NR₂, where the two R groups are takentogether and with the nitrogen atom to which they are attached to form aheterocyclic or substituted heterocyclic ring.

“Sulfonyl” refers to the groups —SO₂-alkyl, —SO₂-substituted alkyl,—SO₂-alkenyl, —SO₂-substituted alkenyl, —SO₂-alkynyl, —SO₂-substitutedalkynyl, —SO₂-aryl, —SO₂-substituted aryl, —SO₂-heteroaryl,—SO₂-substituted heteroaryl, —SO₂-heterocyclic, and —SO₂-substitutedheterocyclic.

“Carbonylalkylenealkoxy” refers to the group —C(═O)—(CH₂)_(n)—OR where Ris a substituted or unsubstituted alkyl and n is an integer from 1 to100, more preferably n is an integer from 1 to 10 or 1 to 5.

“Halo” or “halogen” refers to elements of the Group 17 series havingatomic number 9 to 85. Preferred halo groups include the radicals offluorine, chlorine, bromine and iodine. Where a residue is substitutedwith more than one halogen, it may be referred to by using a prefixcorresponding to the number of halogen moieties attached, e.g.,dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkylsubstituted with two (“di”) or three (“tri”) halo groups, which may bebut are not necessarily the same halogen; thus 4-chloro-3-fluorophenylis within the scope of dihaloaryl. An alkyl group in which each H isreplaced with a halo group is referred to as a “perhaloalkyl.” Apreferred perhaloalkyl group is trifluoroalkyl (—CF₃). Similarly,“perhaloalkoxy” refers to an alkoxy group in which a halogen takes theplace of each H in the hydrocarbon making up the alkyl moiety of thealkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy(—OCF₃).

“Carbonyl” refers to the group C═O.

“Cyano” refers to the group —CN.

“Oxo” refers to the moiety ═O.

“Nitro” refers to the group —NO₂.

“Thioalkyl” refers to the groups —S-alkyl.

“Alkylsulfonylamino” refers to the groups —R¹SO₂NR_(a)R_(b) where R_(a)and R_(b) are independently selected from the group consisting of H,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, or the R_(a) andR_(b) groups can be joined together with the nitrogen atom to form aheterocyclic or substituted heterocyclic ring and R¹ is an alkyl group.

“Carbonylalkoxy” refers to as used herein refers to the groups—C(O)O-alkyl, —C(O)O-substituted alkyl, —C(O)O-aryl, —C(O)O-substitutedaryl, —C(O)O-alkenyl, —C(O)O-substituted alkenyl, —C(O)O-alkynyl,—C(O)O-substituted alkynyl, —C(O)O-heteroaryl, —C(O)O-substitutedheteroaryl, —C(O)O-heterocyclic or —C(O)O-substituted heterocyclic.

“Geminal” refers to the relationship between two moieties that areattached to the same atom. For example, in the residue —CH₂—CHR¹R², R¹and R² are geminal and R¹ may be referred to as a geminal R group to R².

“Vicinal” refers to the relationship between two moieties that areattached to adjacent atoms. For example, in the residue —CHR¹—CH₂R², R¹and R² are vicinal and R¹ may be referred to as a vicinal R group to R².

A composition of “substantially pure” compound means that thecomposition contains no more than 15% or preferably no more than 10% ormore preferably no more than 5% or even more preferably no more than 3%and most preferably no more than 1% impurity, which impurity may be thecompound in a different stereochemical form. For instance, a compositionof substantially pure S compound means that the composition contains nomore than 15% or no more than 10% or no more than 5% or no more than 3%or no more than 1% of the R form of the compound.

Compounds of the Invention

Compounds according to the invention are detailed herein, including inthe Brief Summary of the Invention and the appended claims. Theinvention includes the use of all of the compounds described herein,including any and all stereoisomers, salts and solvates of the compoundsdescribed herein, as well as methods of making such compounds.

Compounds of the formula (A) are provided:

wherein:

R¹ is H, hydroxyl, nitro, cyano, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;

R² is H, hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl, substitutedor unsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, C₁-C₈ alkoxy, aryloxy, carboxyl, carbonylalkoxy, thiol,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaralkyl, thioalkyl, substituted or unsubstituted amino, acylamino,aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl,sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino oracyl;

X is OH, H, C₁-C₈ unsubstituted alkyl or is taken together with Y toform a cyclic moiety of the formula —OCH₂CH₂O—;

Y is halo, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, C₁-C₈ alkyl substituted with a carbonylalkoxy,carboxyl or acylamino moiety or is taken together with X to form acyclic moiety of the formula —OCH₂CH₂O—; and

R³ is a substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl or a substituted or unsubstitutedheterocyclyl;

or a salt or solvate thereof.

In one variation of formula (A), R¹ is C₁-C₈ unsubstituted alkyl; R² isC₁-C₈ unsubstituted alkyl, H or halo and R³ is a substituted orunsubstituted aryl or a substituted or unsubstituted heteroaryl. In aparticular variation of formula (A), R¹ is methyl, ethyl or isopropyl;R² is methyl, H or chloro and R³ is a substituted or unsubstituted arylor a substituted or unsubstituted heteroaryl. When R³ is anunsubstituted aryl in one variation it is a phenyl moiety. When R³ is asubstituted aryl in one aspect it is a substituted phenyl. When R³ is asubstituted phenyl, the phenyl may be substituted with one or more thanone substituent. For example, on one variation, R³ is a monosubstitutedphenyl where the substituent is a halo group. In another variation, R³is a disubstituted phenyl substituent with two halo groups which may bethe same or different. In a particular variation, R³ is 4-fluorophenyl,2-fluorophenyl, 4-chlorophenyl, 2-chlorophenyl, 4-methoxyphenyl or2,4-difluorophenyl. When R³ is an unsubstituted heteroaryl in onevariation it is a heteroaryl containing an annular nitrogen atom. In oneaspect, when R³ is unsubstituted heteroaryl the heteroaryl contains onlynitrogen and carbon annular atoms. In a particular variation, R³ is anunsubstituted heteroaryl selected from pyridyl or pyrimidinyl andwherein such groups may be bound to the parent structure at anyavailable ring position. For example, in one variation, R³ is 4-pyridyl,3-pyridyl or 6-pyrimidyl. When R³ is a substituted heteroaryl in oneaspect it is a substituted pyridyl. When R³ is a substituted pyridyl,the pyridyl may be substituted with one or more than one substituent andthe substituted pyridyl may be bound to the parent structure at anyavailable ring position. For example, on one variation, R³ is amonosubstituted pyridyl where the substituent is a C₁-C₈ unsubstitutedalkyl (e.g., methyl). In a particular variation, R³ is2-methyl-4-pyridyl, 6-methyl-3-pyridyl or 3-methyl-4-pyridyl.

In one variation of formula (A), X is OH and Y is an unsubstituted aryl.In one aspect, Y is phenyl. In another variation, X is H and Y is aC₁-C₈ alkyl substituted with a carbonylalkoxy, carboxyl or acylaminomoiety. In one aspect, Y is a methylene substituted with acarbonylalkoxy, carboxyl or acylamino moiety. In a particular aspect, Yis a moiety selected from the following structures

where R⁴ is a C₁-C₈ unsubstituted alkyl. In one variation, Y is a moietyselected from the following structures

where R⁴ is a C₁-C₈ unsubstituted alkyl and X is H. In anothervariation, X is an unsubstituted C₁-C₈ alkyl and Y is halo. In aparticular aspect, Y is fluoro.

The invention also embraces compounds of the formula (I):

or a salt or solvate thereof, where R¹, R² and R³ are as defined forformula (A). In one variation of formula (I), R¹ and R² areindependently an unsubstituted C₁-C₈ alkyl. In another variation offormula (I), R³ is a substituted aryl, such as a substituted phenylgroup, or an unsubstituted heteroaryl, such as pyridyl. In one aspect,R³ is a halo substituted phenyl or pyridyl moiety. When R³ is a halosubstituted phenyl, in a particular variation the phenyl is substitutedwith a fluoro that may be at any position on the phenyl ring. When R³ isa pyridyl group it may be bound to the parent structure at any availablering position. In a particular aspect, R³ is 4-pyridyl. In a particularvariation of formula (I), R¹ and R² are independently an unsubstitutedC₁-C₈ alkyl and R³ is a substituted aryl or an unsubstituted heteroaryl.In one variation, R¹ and R² are each methyl and R³ is a substituted arylor unsubstituted heteroaryl. In a particular variation of formula (I),R¹ and R² are each methyl and R³ is a fluoro substituted phenyl orpyridyl moiety.

The invention also embraces compounds of the formula (II):

or a salt or solvate thereof, where R¹, R² and R³ are as defined forformula (A). In one variation of formula (II), R¹ is an unsubstitutedC₁-C₈ alkyl (e.g., methyl). In another variation of formula (II), R² isH, an unsubstituted C₁-C₈ alkyl (e.g., methyl) or halo (e.g., chloro).In one aspect of formula (II), R¹ is an unsubstituted C₁-C₈ alkyl and R²is H, an unsubstituted C₁-C₈ alkyl or halo. In a particular variation offormula (II), R¹ is methyl and R² is H, methyl or chloro. In onevariation of formula (II), R¹ and R² are independently an unsubstitutedC₁-C₈ alkyl such as methyl. In one variation of formula (II), R³ is asubstituted or unsubstituted aryl or a substituted or unsubstitutedheteroaryl, such as those listed herein for formula (A). For example,compounds of the formula (II) are intended wherein R³ is anunsubstituted aryl, which in one variation is a phenyl moiety. Compoundsof the formula (II) are also intended wherein R³ is a substituted aryl,which in one aspect it is a substituted phenyl. When R³ is a substitutedphenyl, the phenyl may be substituted with one or more than onesubstituent. For example, on one variation, R³ is a monosubstitutedphenyl where the substituent is a halo group. In another variation, R³is a disubstituted phenyl substituent with two halo groups which may bethe same or different. In a particular variation, R³ is 4-fluorophenyl,2-fluorophenyl, 4-chlorophenyl, 2-chlorophenyl, 4-methoxyphenyl or2,4-difluorophenyl. Compounds of formula (II) are provided where R³ isan unsubstituted heteroaryl, which in one variation is a heteroarylcontaining an annular nitrogen atom. In one aspect, when R³ isunsubstituted heteroaryl the heteroaryl contains only nitrogen andcarbon annular atoms. In a particular variation of formula (II), R³ isan unsubstituted heteroaryl selected from pyridyl or pyrimidinyl andwherein such groups may be bound to the parent structure at anyavailable ring position. For example, in one variation of formula (II),R³ is 4-pyridyl, 3-pyridyl or 6-pyrimidyl. When R³ is a substitutedheteroaryl in one aspect it is a substituted pyridyl. When R³ is asubstituted pyridyl, the pyridyl may be substituted with one or morethan one substituent and the substituted pyridyl may be bound to theparent structure at any available ring position. For example, in onevariation of formula (II), R³ is a monosubstituted pyridyl where thesubstituent is a C₁-C₈ unsubstituted alkyl (e.g., methyl). In aparticular variation of formula (II), R³ is 2-methyl-4-pyridyl,6-methyl-3-pyridyl or 3-methyl-4-pyridyl. In another variation offormula (II), R³ is a substituted aryl, such as a substituted phenylgroup. In one aspect, R³ is a halo substituted phenyl. When R³ is a halosubstituted phenyl, in a particular variation the phenyl is substitutedwith a fluoro or chloro that may be at any position on the phenyl ring.In a further variation of formula (II), R¹ is an unsubstituted C₁-C₈alkyl; R² is H, an unsubstituted C₁-C₈alkyl or halo and R³ is asubstituted or unsubstituted phenyl, a substituted or unsubstitutedpyridyl or an unsubstituted pyrimidyl. In a particular variation,compounds of formula (II) are provided where R¹ is methyl, R² is H,methyl or chloro and R³ is a substituted or unsubstituted phenyl, asubstituted or unsubstituted pyridyl or an unsubstituted pyrimidyl.

Compounds of the formula (III) are also provided:

or a salt or solvate thereof, where R¹, R² and R³ are as detailed forformula (A) and R⁴ is an unsubstituted C₁-C₈ alkyl. In one variation offormula (III), R¹ is an unsubstituted C₁-C₈ alkyl. In one variation offormula (III), R₂ is an unsubstituted C₁-C₈ alkyl or halo. In onevariation of formula (III), R¹ and R² are independently an unsubstitutedC₁-C₈ alkyl (e.g., methyl or ethyl). In one variation of formula (III),R¹ is an unsubstituted C₁-C₈ alkyl (e.g., methyl or ethyl) and R² is anunsubstituted C₁-C₈ alkyl or halo. In a particular variation of formula(III), R⁴ is a C₁-C₄ unsubstituted alkyl. In a further variation offormula (III), R⁴ is methyl, ethyl, propyl or butyl. In one aspect, R⁴is iso-propyl. In another aspect, R⁴ is tert-butyl. In a particularvariation of formula (III), R¹ is an unsubstituted C₁-C₈ alkyl; R² is anunsubstituted C₁-C₈ alkyl or halo and R⁴ is a C₁-C₄ unsubstituted alkyl.In another variation of formula (III), R³ is a substituted orunsubstituted aryl or a substituted or unsubstituted heteroaryl, such asthose listed herein for formula (A). For example, compounds of theformula (III) are intended wherein R³ is a substituted aryl, which inone aspect it is a substituted phenyl. When R³ is a substituted phenyl,the phenyl may be substituted with one or more than one substituent. Forexample, on one variation, R³ is a monosubstituted phenyl where thesubstituent is a halo group. In another variation, R³ is adihalo-substituted phenyl wherein the halo moieties may be the same ordifferent. In a particular variation, R³ is 4-fluorophenyl,4-chlorophenyl, 2,4-difluorophenyl or 4-methoxyphenyl. Compounds offormula (III) are also provided where R³ is an unsubstituted heteroaryl,which in one variation is a heteroaryl containing an annular nitrogenatom. In one aspect, when R³ is unsubstituted heteroaryl the heteroarylcontains only nitrogen and carbon annular atoms. In a particularvariation of formula (III), R³ is an unsubstituted heteroaryl selectedfrom pyridyl or pyrimidinyl and wherein such groups may be bound to theparent structure at any available ring position. For example, in onevariation of formula (III), R³ is 4-pyridyl, 3-pyridyl or 6-pyrimidyl.When R³ is a substituted heteroaryl in one aspect it is a substitutedpyridyl. When R³ is a substituted pyridyl, the pyridyl may besubstituted with one or more than one substituent and the substitutedpyridyl may be bound to the parent structure at any available ringposition. For example, in one variation of formula (III), R³ is amonosubstituted pyridyl where the substituent is a C₁-C₈ unsubstitutedalkyl (e.g., methyl). In a particular variation of formula (III), R³ is2-methyl-4-pyridyl, 6-methyl-3-pyridyl or 3-methyl-4-pyridyl. In afurther variation of formula (III), R¹ is an unsubstituted C₁-C₈ alkyl;R² is an unsubstituted C₁-C₈alkyl or halo; R⁴ is a C₁-C₄ unsubstitutedalkyl and R³ is a substituted phenyl, a substituted or unsubstitutedpyridyl or an unsubstituted pyrimidyl. In a particular variation,compounds of formula (III) are provided where R¹ is methyl or ethyl, R²is methyl or chloro; R⁴ is methyl, ethyl, isopropyl or tert-butyl and R³is a substituted phenyl, a substituted or unsubstituted pyridyl or anunsubstituted pyrimidyl.

Also provided herein are compounds of the formula (IV):

or a salt of solvate thereof, where R¹, R² and R³ are as detailed forformula (A). In one variation of formula (IV), R¹ is an unsubstitutedC₁-C₈ alkyl (e.g., methyl). In another variation of formula (IV), R² isunsubstituted C₁-C₈ alkyl (e.g., methyl) or halo (e.g., chloro). In aparticular variation of formula (IV), R¹ is an unsubstituted C₁-C₈ alkyland R² is unsubstituted C₁-C₈ alkyl or halo. In another variation offormula (IV), R¹ and R² are independently an unsubstituted C₁-C₈ alkyl(e.g., methyl). In one variation of formula (IV), R³ is a substituted orunsubstituted aryl or a substituted or unsubstituted heteroaryl, such asthose listed herein for formula (A). For example, compounds of theformula (IV) are intended wherein R³ is a substituted aryl, which in oneaspect it is a substituted phenyl. When R³ is a substituted phenyl, thephenyl may be substituted with one or more than one substituent. Forexample, on one variation, R³ is a monosubstituted phenyl where thesubstituent is a halo group. In another variation, R³ is a disubstitutedphenyl substituent with two halo groups which may be the same ordifferent. In a particular variation, R³ is 4-fluorophenyl,2-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl or 2,4-difluorophenyl.Compounds of formula (IV) are also provided where R³ is an unsubstitutedheteroaryl, which in one variation is a heteroaryl containing an annularnitrogen atom. In one aspect, when R³ is unsubstituted heteroaryl theheteroaryl contains only nitrogen and carbon annular atoms. In aparticular variation of formula (IV), R³ is an unsubstituted heteroarylselected from pyridyl or pyrimidinyl and wherein such groups may bebound to the parent structure at any available ring position. Forexample, in one variation of formula (IV), R³ is 4-pyridyl, 3-pyridyl or6-pyrimidyl. When R³ is a substituted heteroaryl in one aspect it is asubstituted pyridyl. When R³ is a substituted pyridyl, the pyridyl maybe substituted with one or more than one substituent and the substitutedpyridyl may be bound to the parent structure at any available ringposition. For example, in one variation of formula (IV), R³ is amonosubstituted pyridyl where the substituent is a C₁-C₈ unsubstitutedalkyl (e.g., methyl). In a particular variation of formula (IV), R³ is2-methyl-4-pyridyl, 6-methyl-3-pyridyl or 3-methyl-4-pyridyl. In onevariation of formula (IV), R¹ is an unsubstituted C₁-C₈ alkyl, R² isunsubstituted C₁-C₈ alkyl or halo and R³ is a substituted phenyl, asubstituted or unsubstituted pyridyl or an unsubstituted pyrimidyl. In aparticular variation of formula (IV), R¹ and R² are independently anunsubstituted C₁-C₈ alkyl and R³ is a substituted phenyl, a substitutedor unsubstituted pyridyl or an unsubstituted pyrimidyl.

Additional compounds detailed herein are of the formula (V):

or a salt of solvate thereof, where R¹, R² and R³ are as detailed forformula (A). In one variation of formula (V), R¹ is an unsubstitutedC₁-C₈ alkyl (e.g., methyl or ethyl). In another variation of formula(V), R² is unsubstituted C₁-C₈ alkyl (e.g., methyl) or halo (e.g.,chloro). In a particular variation of formula (V), R¹ is anunsubstituted C₁-C₈ alkyl and R² is unsubstituted C₁-C₈ alkyl or halo.In another variation of formula (V), R¹ and R² are independently anunsubstituted C₁-C₈ alkyl. In one variation of formula (V), R³ is asubstituted or unsubstituted aryl or a substituted or unsubstitutedheteroaryl, such as those listed herein for formula (A). For example,compounds of the formula (V) are intended wherein R³ is a substitutedaryl, which in one aspect it is a substituted phenyl. When R³ is asubstituted phenyl, the phenyl may be substituted with one or more thanone substituent. For example, on one variation, R³ is a monosubstitutedphenyl where the substituent is a halo group. In another variation, R³is a disubstituted phenyl substituent with two halo groups which may bethe same or different. In a particular variation, R³ is 4-fluorophenyl,2-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl or 2,4-difluorophenyl.Compounds of formula (V) are also provided where R³ is an unsubstitutedheteroaryl, which in one variation is a heteroaryl containing an annularnitrogen atom. In one aspect, when R³ is unsubstituted heteroaryl theheteroaryl contains only nitrogen and carbon annular atoms. In aparticular variation of formula (V), R³ is an unsubstituted heteroarylselected from pyridyl or pyrimidinyl and wherein such groups may bebound to the parent structure at any available ring position. Forexample, in one variation of formula (V), R³ is 4-pyridyl, 3-pyridyl or6-pyrimidyl. When R³ is a substituted heteroaryl in one aspect it is asubstituted pyridyl. When R³ is a substituted pyridyl, the pyridyl maybe substituted with one or more than one substituent and the substitutedpyridyl may be bound to the parent structure at any available ringposition. For example, in one variation of formula (V), R³ is amonosubstituted pyridyl where the substituent is a C₁-C₈ unsubstitutedalkyl (e.g., methyl). In a particular variation of formula (V), R³ is2-methyl-4-pyridyl, 6-methyl-3-pyridyl or 3-methyl-4-pyridyl. In onevariation of formula (V), R¹ is an unsubstituted C₁-C₈ alkyl, R² isunsubstituted C₁-C₈ alkyl or halo and R³ is a substituted phenyl, asubstituted or unsubstituted pyridyl or an unsubstituted pyrimidyl.

Compounds of the formula (VI) are also detailed herein:

or a salt or solvate thereof, where R¹, R² and R³ are as defined forformula (A). In one variation of formula (VI), R¹ is an unsubstitutedC₁-C₈ alkyl (e.g., methyl, ethyl or isopropyl). In another variation offormula (VI), R² is unsubstituted C₁-C₈ alkyl (e.g., methyl) or halo(e.g., chloro). In a particular variation of formula (VI), R¹ is anunsubstituted C₁-C₈ alkyl and R² is unsubstituted C₁-C₈ alkyl or halo.In another variation of formula (VI), R¹ and R² are independently anunsubstituted C₁-C₈ alkyl. In one variation of formula (VI), R³ is asubstituted or unsubstituted aryl or a substituted or unsubstitutedheteroaryl, such as those listed herein for formula (A). For example,compounds of the formula (VI) are intended wherein R³ is a substitutedaryl, which in one aspect it is a substituted phenyl. When R³ is asubstituted phenyl, the phenyl may be substituted with one or more thanone substituent. For example, on one variation, R³ is a monosubstitutedphenyl where the substituent is a halo group. In another variation, R³is a disubstituted phenyl substituent with two halo groups which may bethe same or different. In a particular variation, R³ is 4-fluorophenyl,4-chlorophenyl, 4-methoxyphenyl or 2,4-difluorophenyl. Compounds offormula (VI) are also provided where R³ is an unsubstituted heteroaryl,which in one variation is a heteroaryl containing an annular nitrogenatom. In one aspect, when R³ is unsubstituted heteroaryl the heteroarylcontains only nitrogen and carbon annular atoms. In a particularvariation of formula (VI), R³ is an unsubstituted heteroaryl selectedfrom pyridyl or pyrimidinyl and wherein such groups may be bound to theparent structure at any available ring position. For example, in onevariation of formula (VI), R³ is 4-pyridyl, 3-pyridyl or 6-pyrimidyl.When R³ is a substituted heteroaryl in one aspect it is a substitutedpyridyl. When R³ is a substituted pyridyl, the pyridyl may besubstituted with one or more than one substituent and the substitutedpyridyl may be bound to the parent structure at any available ringposition. For example, in one variation of formula (VI), R³ is amonosubstituted pyridyl where the substituent is a C₁-C₈ unsubstitutedalkyl (e.g., methyl). In a particular variation of formula (VI), R³ is6-methyl-3-pyridyl or 3-methyl-4-pyridyl. In one variation of formula(VI), R¹ is an unsubstituted C₁-C₈ alkyl, R² is unsubstituted C₁-C₈alkyl or halo and R³ is a substituted phenyl, a substituted orunsubstituted pyridyl or an unsubstituted pyrimidyl.

Compounds of the formula (VII) are also provided:

or a salt or solvate thereof, where R¹, R² and R³ are as defined forformula (A). In one variation of formula (VII), R¹ and R² are each aC₁-C₈ unsubstituted alkyl group. In another variation of formula (VII),R³ is an unsubstituted heteroaryl such as pyridyl. In a particularvariation of formula (VII), R¹ and R² are each a C₁-C₈ unsubstitutedalkyl group and R³ is an unsubstituted heteroaryl.

Compounds of the formula (A) and in particular compounds of the formulae(I)-(VII) are described as new histamine receptor modulators. Compoundsof the invention may also find use in treating neurodegenerativediseases.

Examples of compounds according to the invention are depicted inTable 1. The compounds depicted may be present as salts even if saltsare not depicted and it is understood that the invention embraces allsalts and solvates of the compounds depicted here, as well as thenon-salt and non-solvate form of the compound, as is well understood bythe skilled artisan.

TABLE 1 Representative Compounds According to the Invention. Comp. #Compound Structure  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

Compound No. Compound Name  12-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(4-fluorophenyl)-1-phenylethanol  22,8-Dimethyl-5-((2-phenyl-1,3-dioxolan-2-yl)methyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole  35-((2-(4-Fluorophenyl)-1,3-dioxolan-2-yl)methyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole  48-Chloro-5-((2-(4-fluorophenyl)-1,3-dioxolan-2-yl)methyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole  58-Chloro-5-((2-(4-chlorophenyl)-1,3-dioxolan-2-yl)methyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole  6 Ethyl4-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(4-fluorophenyl)butanoate  74-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(4-fluorophenyl)butanoic acid  84-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(4-fluorophenyl)-N-methylbutanamide  95-(2-Fluoro-2-(pyridin-4-yl)propyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 108-Chloro-5-(2-fluoro-2-(pyridin-4-yl)propyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 112-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-phenyl-1-(pyridin-4-yl)EtOH 122-Methyl-5-((2-(pyridin-4-yl)-1,3-dioxolan-2-yl)methyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 132,8-Dimethyl-5-((2-(pyridin-3-yl)-1,3-dioxolan-2-yl)methyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 145-((2-(2,4-Difluorophenyl)-1,3-dioxolan-2-yl)methyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 152,8-Dimethyl-5-((2-(pyrimidin-4-yl)-1,3-dioxolan-2-yl)methyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 168-Chloro-5-((2-(2-chlorophenyl)-1,3-dioxolan-2-yl)methyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 178-Chloro-2-methyl-5-((2-(2-methylpyridin-4-yl)-1,3-dioxolan-2-yl)methyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 188-Chloro-5-((2-(2-fluorophenyl)-1,3-dioxolan-2-yl)methyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 198-Chloro-2-methyl-5-((2-(6-methylpyridin-3-yl)-1,3-dioxolan-2-yl)methyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 208-Chloro-2-methyl-5-((2-(3-methylpyridin-4-yl)-1,3-dioxolan-2-yl)methyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 218-Chloro-5-((2-(4-methoxyphenyl)-1,3-dioxolan-2-yl)methyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 22 Isopropyl4-(8-chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(4-methoxyphenyl)butanoate 23 Isopropyl4-(8-chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(4-chlorophenyl)butanoate 24 Isopropyl4-(8-chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(6-methylpyridin-3-yl)butanoate 25 tert-Butyl4-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(4-fluorophenyl)butanoate 26 Methyl3-(2,4-difluorophenyl)-4-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)butanoate 27 Ethyl4-(8-chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(3-methylpyridin-4-yl)butanoate 28 Ethyl4-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(pyridin-4-yl)butanoate 29 Ethyl4-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(pyridin-3-yl)butanoate 30 Ethyl4-(8-chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(pyrimidin-4-yl)butanoate 31 Ethyl4-(2-ethyl-8-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(2-methylpyridin-4-yl)butanoate 324-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(pyridin-4-yl)butanoic acid 334-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(pyridin-3-yl)butanoic acid 344-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(pyrimidin-4-yl)butanoic acid 354-(2-Ethyl-8-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(2-methylpyridin-4-yl)butanoic acid 364-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(6-methylpyridin-3-yl)butanoic acid 374-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(2-fluorophenyl)butanoic acid 383-(2,4-Difluorophenyl)-4-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)butanoic acid 394-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(3-methylpyridin-4-yl)butanoic acid 404-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(4-methoxyphenyl)butanoic acid 414-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(4-chlorophenyl)butanoic acid 424-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-N-methyl-3-(pyridin-4-yl)butanamide 434-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-N-methyl-3-(pyridin-3-yl)butanamide 444-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-N-methyl-3-(pyrimidin-4-yl)butanamide 454-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-N-methyl-3-(2-methylpyridin-4-yl)butanamide 464-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-N-methyl-3-(6-methylpyridin-3-yl)butanamide 474-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(2-fluorophenyl)-N-methylbutanamide 483-(2,4-Difluorophenyl)-4-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-N-methylbutanamide 494-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-N-methyl-3-(3-methylpyridin-4-yl)butanamide 504-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(4-methoxyphenyl)-N-methylbutanamide 514-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(4-chlorophenyl)-N-methylbutanamide 525-(2-Fluoro-2-(4-fluorophenyl)propyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 538-Chloro-5-(2-(2,4-difluorophenyl)-2-fluoropropyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 545-(2-(4-Chlorophenyl)-2-fluoropropyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 558-Chloro-5-(2-fluoro-2-(pyridin-3-yl)propyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 562-Ethyl-5-(2-fluoro-2-(pyridin-3-yl)propyl)-8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 575-(2-Fluoro-2-(pyrimidin-4-yl)propyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 588-Chloro-5-(2-fluoro-2-(6-methylpyridin-3-yl)propyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 595-(2-Fluoro-2-(2-methylpyridin-4-yl)propyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 602-Cyclopropyl-5-(2-fluoro-2-(4-methoxyphenyl)propyl)-8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 618-Chloro-5-(2-fluoro-2-(3-methylpyridin-4-yl)propyl)-2-isopropyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 625-(2-Fluoro-2-(pyridin-4-yl)ethyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole

Pharmaceutical compositions of any of the compounds detailed herein areembraced by this invention. Thus, the invention includes pharmaceuticalcompositions comprising a compound of the invention or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier or excipient. In one aspect, the pharmaceuticallyacceptable salt is an acid addition salt, such as a salt formed with aninorganic or organic acid. Pharmaceutical compositions according to theinvention may take a form suitable for oral, buccal, parenteral, nasal,topical or rectal administration, or a form suitable for administrationby inhalation.

A compound as detailed herein may in one aspect be in a purified formand compositions comprising a compound in purified forms are detailedherein. Compositions comprising a compound as detailed herein or a saltthereof are provided, such as compositions of substantially purecompounds. In some embodiments, a composition containing a compound asdetailed herein or a salt thereof is in substantially pure form. Unlessotherwise stated, “substantially pure” intends a composition thatcontains no more than 35% impurity, wherein the impurity denotes acompound other than the compound comprising the majority of thecomposition or a salt thereof. Taking compound 1 as an example, acomposition of substantially pure compound 1 intends a composition thatcontains no more than 35% impurity, wherein the impurity denotes acompound other than compound 1 or a salt thereof. In one variation, acomposition of substantially pure compound or a salt thereof is providedwherein the composition contains no more than 25% impurity. In anothervariation, a composition of substantially pure compound or a saltthereof is provided wherein the composition contains or no more than 20%impurity. In still another variation, a composition of substantiallypure compound or a salt thereof is provided wherein the compositioncontains or no more than 10% impurity. In a further variation, acomposition of substantially pure compound or a salt thereof is providedwherein the composition contains or no more than 5% impurity. In anothervariation, a composition of substantially pure compound or a saltthereof is provided wherein the composition contains or no more than 3%impurity. In still another variation, a composition of substantiallypure compound or a salt thereof is provided wherein the compositioncontains or no more than 1% impurity. In a further variation, acomposition of substantially pure compound or a salt thereof is providedwherein the composition contains or no more than 0.5% impurity.

In one variation, the compounds herein are synthetic compounds preparedfor administration to an individual. In another variation, compositionsare provided containing a compound in substantially pure form. Inanother variation, the invention embraces pharmaceutical compositionscomprising a compound detailed herein and a pharmaceutically acceptablecarrier. In another variation, methods of administering a compound areprovided. The purified forms, pharmaceutical compositions and methods ofadministering the compounds are suitable for any compound or formthereof detailed herein.

General Description of Biological Assays

The binding properties of compounds disclosed herein to a panel ofaminergic G protein-coupled receptors including adrenergic receptors,dopamine receptors, serotonin receptors, histamine receptors and animidazoline receptor may be determined. Binding properties may beassessed by methods known in the art, such as competitive bindingassays. In one variation, compounds are assessed by the binding assaysdetailed herein. Compounds disclosed herein may also be tested incell-based assays or in in vivo models for further characterization. Inone aspect, compounds disclosed herein are of any formula detailedherein and further display one or more of the following characteristics:inhibition of binding of a ligand to an adrenergic receptor (e.g.,α_(1D), α_(2A) and α_(2B)), inhibition of binding of a ligand to aserotonin receptor (e.g., 5-HT_(2A), 5-HT_(2C), 5-HT₆ and 5-HT₇),inhibition of binding of a ligand to a dopamine receptor (e.g., D_(2L)),and inhibition of binding of a ligand to a histamine receptor (e.g., H₁,H₂ and H₃); agonist/antagonist activity to a serotonin receptor (e.g.,5-HT_(2A), 5-HT₆); agonist/antagonist activity to a dopamine receptor(e.g., D_(2L), D_(2S)); agonist/antagonist activity to a histaminereceptor (e.g., H₁); activity in a neurite outgrowth assay; efficacy ina preclinical model of memory dysfunction associated with cholinergicdysfunction/hypofunction; efficacy in a preclinical model of attentionimpulsivity and executive function, and efficacy in a preclinical modelof schizophrenia.

In one variation, inhibition of binding of a ligand to a receptor ismeasured in the assays described herein. In another variation,inhibition of binding of a ligand is measured in an assay known in theart. In one variation, binding of a ligand to a receptor is inhibited byat least about 80% as determined in a suitable assay known in the artsuch as the assays described herein. In one variation, binding of aligand to a receptor is inhibited by greater than about any one of 80%,85%, 90%, 95%, 100%, or between about 85% and about 95% or between about90 and about 100% as determined in a suitable assay known in the artsuch as the assays described herein. In one variation, binding of aligand to a receptor is inhibited by at least about 80%±20% asdetermined in an assay known in the art.

In one variation, a compound of the invention inhibits binding of aligand to at least one receptor and as many as eleven as detailed herein(e.g., a_(1D), a_(2A), a_(2B), 5-HT_(2A), 5-HT_(2C), 5-HT₆, 5-HT₇,D_(2L), H₁, H₂, H₃). In one variation, a compound of the inventioninhibits binding of a ligand to at least one receptor and as many aseleven as detailed herein (e.g., a_(1D), a_(2A), a_(2B), 5-HT_(2A),5-HT_(2C), 5-HT₆, 5-HT₇, D₂, H₁, H₂, H₃). In one variation, a compoundof the invention inhibits binding of a ligand to at least one and asmany as eleven receptors detailed herein and further displays agonist orantagonist activity to one or more receptors detailed herein (e.g.,serotonin receptor 5-HT_(2A), serotonin receptor 5-HT₆, dopaminereceptor D_(2L), dopamine receptor D_(2S) and histamine receptor H₁) asmeasured in the assays described herein. In one variation, agonistresponse of serotonin receptor 5-HT_(2A) is inhibited by compounds ofthe invention by at least about any one of 50%, 50%, 70%, 80%, 90%,100%, 110%, 120%, 130%, 140%, 150% as determined in a suitable assaysuch as the assay described herein.

In one variation, a compound of the invention displays the abovedescribed neurotransmitter receptor binding profile, e.g., inhibitsbinding of a ligand to at least one receptor and as many as eleven asdetailed herein and further stimulates neurite outgrowth, e.g., asmeasured by the assays described herein. Certain compounds of theinvention showed activity in neurite outgrowth assays using primaryneurons in culture. Data is presented indicating that a compound of theinvention has activity comparable in magnitude to that of naturallyoccurring prototypical neurotrophic proteins such as brain derivedneurotrophic factor (BDNF) and nerve growth factor (NGF). Notably,neurite outgrowth plays a critical part of new synaptogenesis, which isbeneficial for the treatment of neuronal disorders. In one variation,neuronal disorders include ADHD. In one variation, neurite outgrowth isobserved with a potency of about 1 μM as measured in a suitable assayknown in the art such as the assays described herein. In anothervariation, neurite outgrowth is observed with a potency of about 500 nM.In a further variation, neurite outgrowth is observed with a potency ofabout 50 nM. In another variation, neurite outgrowth is observed with apotency of about 5 nM.

In another variation, a compound of the invention inhibits binding of aligand to at least one receptor and as many as eleven as detailedherein, further displays agonist or antagonist activity to one or morereceptors detailed herein and further stimulates neurite outgrowth.

In a further variation, a compound of the invention inhibits binding ofa ligand to at least one and as many as eleven receptors as detailedherein and/or display the above described neurotransmitter receptorbinding profile and further shows efficacy in a preclinical model ofmemory dysfunction associated with cholinergic dysfunction/hypofunction,and in preclinical models of attention/impulsivity and executivefunction, e.g., shows pro-cognitive effects in a preclinical model ofmemory dysfunction. Compounds of the invention have been shown to beeffective in a preclinical model of memory dysfunction associated withcholinergic hypofunction. As H₁ antagonism may contribute to sedation,weight gain and reduced cognition, low affinity (less than about 80%inhibition of binding of Pyrilamine at 1 μM in the assay describedherein) for this receptor may be associated with pro-cognitive effectsand a more desirable side effect profile. Furthermore, compounds of theinvention with increased potency as a 5-HT₆ antagonist may havecognition-enhancing effects as serotonin acting through this receptormay impair memory.

In another variation, a compound of the invention inhibits binding of aligand to at least one and as many as eleven receptors as detailedherein, further shows efficacy in a preclinical model of memorydysfunction associated with cholinergic dysfunction/hypofunction, e.g.,shows pro-cognitive effects in a preclinical model of memorydysfunction, in preclinical models of attention/impulsivity andexecutive function, and further displays agonist or antagonist activityto one or more receptors detailed herein.

In a further variation, a compound of the invention inhibits binding ofa ligand to at least one and as many as eleven receptors as detailedherein, further shows efficacy in a preclinical model of memorydysfunction associated with cholinergic dysfunction/hypofunction, e.g.,shows pro-cognitive effects in a preclinical model of memorydysfunction, and in preclinical models of attention/impulsivity andexecutive function, and further stimulates neurite outgrowth.

In another variation, a compound of the invention inhibits at least oneand as many as eleven receptors as detailed herein, further showsefficacy in a preclinical model of memory dysfunction associated withcholinergic dysfunction/hypofunction, e.g., shows pro-cognitive effectsin a preclinical model of memory dysfunction, in preclinical models ofattention/impulsivity and executive function, further displays agonistor antagonist activity to one or more receptor detailed herein andfurther stimulates neurite outgrowth.

In a further variation, a compound of the invention inhibits binding ofa ligand to at least one and as many as eleven receptors and furtherpossesses anti-psychotic effects as measured in a preclinical model ofschizophrenia, i.e., shows efficacy in a preclinical model ofschizophrenia.

In another variation, a compound of the invention inhibits binding of aligand to at least one and as many as eleven receptors, further showsefficacy in a preclinical model of schizophrenia and further displaysagonist or antagonist activity to one or more receptors detailed herein.

In a further variation, a compound of the invention inhibits binding ofa ligand to at least one and as many as eleven receptors, further showsefficacy in a preclinical model of schizophrenia and further stimulatesneurite outgrowth.

In a further variation, a compound of the invention inhibits binding ofa ligand to at least one and as many as eleven receptors, further showsefficacy in a preclinical model of memory dysfunction associated withcholinergic dysfunction/hypofunction such as enhancement of memoryretention and reduction of memory impairment, and in preclinical modelsof attention/impulsivity and executive function, and further showsefficacy in a preclinical model of schizophrenia.

In another variation, a compound of the invention inhibits binding of aligand to at least one and as many as eleven receptors, further showsefficacy in a preclinical model of schizophrenia, further displaysagonist or antagonist activity to one or more receptors detailed hereinand further shows efficacy in a preclinical model of memory dysfunctionassociated with cholinergic dysfunction/hypofunction such as enhancementof memory retention and reduction of memory impairment, and inpreclinical models of attention/impulsivity and executive function.

In another variation, a compound of the invention inhibits binding of aligand to at least one and as many as eleven receptors, further showsefficacy in a preclinical model of schizophrenia, further stimulatesneurite outgrowth and further shows efficacy in a preclinical model ofmemory dysfunction associated with cholinergic dysfunction/hypofunctionsuch as enhancement of memory retention and reduction of memoryimpairment, and in preclinical models of attention/impulsivity andexecutive function.

In a further variation, a compound of the invention inhibits binding ofa ligand to at least one and as many as eleven receptors detailedherein, further displays agonist or antagonist activity to one or morereceptors detailed herein, further stimulates neurite outgrowth andfurther shows efficacy in a preclinical model of schizophrenia.

In another variation, a compound of the invention inhibits binding of aligand to at least one and as many as eleven receptors, further showsefficacy in a preclinical model of schizophrenia, further displaysagonist or antagonist activity to one or more receptors detailed herein,further stimulates neurite outgrowth and further shows efficacy in apreclinical model of memory dysfunction associated with cholinergicdysfunction/hypofunction such as enhancement of memory retention andreduction of memory impairment, and in preclinical models ofattention/impulsivity and executive function.

In another variation, a compound of the invention stimulates neuriteoutgrowth. In another variation, a compound of the invention showsefficacy in a preclinical model of schizophrenia and further stimulatesneurite outgrowth. In another variation, a compound of the inventionstimulates neurite outgrowth and further shows efficacy in a preclinicalmodel of memory dysfunction associated with cholinergicdysfunction/hypofunction such as enhancement of memory retention andreduction of memory impairment, and in preclinical models ofattention/impulsivity and executive function. In another variation, acompound of the invention shows efficacy in a preclinical model ofschizophrenia, further stimulates neurite outgrowth and further showsefficacy in a preclinical model of memory dysfunction associated withcholinergic dysfunction/hypofunction such as enhancement of memoryretention and reduction of memory impairment, and in preclinical modelsof attention/impulsivity and executive function.

In one aspect, compounds of the invention inhibit binding of a ligand toadrenergic receptors α_(1D), α_(2A), α_(2B) and inhibit binding of aligand to serotonin receptor 5-HT₆. In another variation, compounds ofthe invention inhibit binding of a ligand to adrenergic receptorsα_(1D), α_(2A), α_(2B), to serotonin receptor 5-HT₆ and to any one ormore of the following receptors: serotonin receptor 5-HT₇, 5-HT_(2A) and5-HT_(2C). In another variation, compounds of the invention inhibitbinding of a ligand to adrenergic receptors α_(1D), α_(2A), α_(2B), toserotonin receptor 5-HT₆ and to any one or more of the followingreceptors: serotonin receptor 5-HT₇, 5-HT_(2A) and 5-HT_(2C) and furthershow weak inhibition of binding of a ligand to histamine receptor H₁and/or H₂. In one variation, compounds of the invention that alsodisplay strong inhibition of binding of a ligand to the serotoninreceptor 5-HT₇ are particularly desired. In another variation, compoundsof the invention inhibit binding of a ligand to adrenergic receptorsα_(1D), α_(2A), α_(2B), to serotonin receptor 5-HT₆ and further showweak inhibition of binding of a ligand to histamine receptor H₁ and/orH₂. Weak inhibition of binding of a ligand to the histamine H₁ receptoris permitted as agonists of this receptor have been implicated instimulating memory as well as weight gain. In one variation, binding tohistamine receptor H₁ is inhibited by less than about 80%. In anothervariation, binding of a ligand to histamine receptor H₁ is inhibited byless than about any of 75%, 70%, 65%, 60%, 55%, or 50% as determined bya suitable assay known in the art such as the assays described herein.

In another variation, compounds of the invention inhibit binding of aligand to a dopamine receptor D₂. In another variation, compounds of theinvention inhibit binding of a ligand to dopamine receptor D_(2L). Inanother variation, compounds of the invention inhibit binding of aligand to dopamine receptor D₂ and to serotonin receptor 5-HT_(2A). Inanother variation, compounds of the invention inhibit binding of aligand to dopamine receptor D_(2L) and to serotonin receptor 5-HT_(2A).In another variation, compounds of the invention inhibit binding of aligand to histamine receptor H₁. In certain aspects, compounds of theinvention further show one or more of the following properties: stronginhibition of binding of a ligand to the serotonin 5-HT₇ receptor,strong inhibition of binding of a ligand to the serotonin 5-HT_(2A)receptor, strong inhibition of binding of a ligand to the serotonin5-HT_(2C) receptor, weak inhibition of binding of a ligand to thehistamine H₁ receptor, weak inhibition of binding of ligands to thehistamine H₂ receptor, and antagonist activity to serotonin receptor5-HT_(2A).

In one variation, compounds of the invention show any of the receptorbinding aspects detailed herein and further display agonist/antagonistactivity to one or more of the following receptors: serotonin receptor5-HT_(2A), serotonin receptor 5-HT₆, dopamine receptor D_(2L), dopaminereceptor D_(2S) and histamine receptor H₁. In one variation, compoundsof the invention show any of the receptor binding aspects detailedherein and further stimulate neurite outgrowth. In one variation,compounds of the invention show any of the receptor binding aspectsdetailed herein and further show efficacy in a preclinical model ofmemory dysfunction associated with cholinergic dysfunction/hypofunction,such as enhancement of memory retention and reduction of memoryimpairment and in preclinical models of attention/impulsivity andexecutive function. In one variation, compounds of the invention showany of the receptor binding aspects detailed herein and further showefficacy in a preclinical model of schizophrenia. In one variation,compounds of the invention show any of the receptor binding aspectsdetailed herein and further show efficacy in any one or more ofagonist/antagonist assays (e.g., to serotonin receptor 5-HT_(2A), 5-HT₆,dopamine receptor D_(2L), dopamine receptor D_(2S) and histaminereceptor H₁), neurite outgrowth, a preclinical model of memorydysfunction associated with cholinergic dysfunction/hypofunction and apreclinical model of schizophrenia.

In some aspects, compounds of the invention inhibit binding of a ligandto adrenergic receptors a_(1D), a_(2A), a_(2B), serotonin receptor 5-HT₆and a dopamine receptor D₂ by at least about 80% as determined in asuitable assay known in the art such as the assays described herein. Inone variation binding is inhibited by at least about 80% as measured ina suitable assay such as the assays described herein. In some aspects,compounds of the invention inhibit binding of a ligand to adrenergicreceptors a_(1D), a_(2A), a_(2B), serotonin receptor 5-HT₆ and dopaminereceptor D_(2L) by at least about 80% as determined in a suitable assayknown in the art such as the assays described herein. In one variationbinding is inhibited by at least about 80% as measured in a suitableassay such as the assays described herein. In one variation, binding ofa ligand to a receptor is inhibited by greater than about any one of80%, 85%, 90%, 95%, 100%, or between about 85% and about 95% or betweenabout 90% and about 100% as determined in a suitable assay known in theart such as the assays described herein.

In some aspects, compounds of the invention display the above describedneurotransmitter receptor binding profile and further show antipsychoticeffects. It is recognized that compounds of the invention have bindingprofiles similar to compounds with antipsychotic activity and severalcompounds of the invention have been shown to be effective in apreclinical model of schizophrenia. In addition, compounds of theinvention might possess the cognitive enhancing properties of dimebonand thus add to the beneficial pharmacology profile of theseantipsychotic molecules. In one variation, compounds of the inventiondisplay the above described neurotransmitter receptor binding profileand further show pro-cognitive effects in a preclinical model of memorydysfunction such as enhancement of memory retention and reduction ofmemory impairment. In another variation, compounds of the inventiondisplay the above described neurotransmitter receptor binding profileand do not show pro-cognitive effects in a preclinical model of memorydysfunction, learning and memory.

In one variation, compounds of the invention demonstrate pro-cognitiveeffects in a preclinical model of memory dysfunction, learning andmemory. In a further variation, compounds of the invention possessanti-psychotic effects in a preclinical model of schizophrenia. In afurther variation, compounds of the invention demonstrate pro-cognitiveeffects in a preclinical model of memory dysfunction, learning andmemory and further possess anti-psychotic effects in a preclinical modelof schizophrenia.

Overview of the Methods

A method of administering a compound of the invention to an individual,such as a human, are detailed herein, wherein the method comprisesadministering to an individual in thereof an effective amount ofcompound or a salt thereof. The compounds described herein may be usedto treat, prevent, delay the onset and/or delay the development ofcognitive disorders, psychotic disorders, neurotransmitter-mediateddisorders and/or neuronal disorders in individuals, such as humans. Inone aspect, the compounds described herein may be used to treat,prevent, delay the onset and/or delay the development of a cognitivedisorder. In one variation, cognitive disorder as used herein includesand intends disorders that contain a cognitive component, such aspsychotic disorders (e.g., schizophrenia) containing a cognitivecomponent (e.g., CIAS). In one variation, cognitive disorder includesADHD. In another aspect, the compounds described herein may be used totreat, prevent, delay the onset and/or delay the development of apsychotic disorder. In one variation, psychotic disorder as used hereinincludes and intends disorders that contain a psychotic component, forexample cognitive disorders (e.g., Alzheimer's disease) that contain apsychotic component (e.g., psychosis of Alzheimer's Disease ordementia). In one variation, methods of improving at least one cognitiveand/or psychotic symptom associated with schizophrenia are provided. Inone aspect, methods of improving cognition in an individual who has oris suspected of having CIAS are provided. In a particular aspect,methods of treating schizophrenia are provided wherein the treatmentprovides for an improvement in one or more negative symptom and/or oneor more positive symptom and/or one or more disorganized symptom ofschizophrenia. In yet another aspect, the compounds described herein maybe used to treat, prevent, delay the onset and/or delay the developmentof a neurotransmitter-mediated disorders disorder. In one aspect, aneurotransmitter-mediated disorder includes ADHD. In one embodiment, theneurotransmitter-mediated disorder includes spinal cord injury, diabeticneuropathy, allergic diseases (including food allergies) and diseasesinvolving geroprotective activity such as age-associated hair loss(alopecia), age-associated weight loss and age-associated visiondisturbances (cataracts). In another variation, theneurotransmitter-mediated disorder includes spinal cord injury, diabeticneuropathy, fibromyalgia and allergic diseases (including foodallergies). In still another embodiment, the neurotransmitter-mediateddisorder includes Alzheimer's disease, Parkinson's Disease, autism,Guillain-Barré syndrome, mild cognitive impairment, multiple sclerosis,stroke and traumatic brain injury. In yet another embodiment, theneurotransmitter-mediated disorder includes schizophrenia, anxiety,bipolar disorders, psychosis, depression and ADHD. In one variation,depression as used herein includes and intends treatment-resistantdepression, depression related to a psychotic disorder, or depressionrelated to a bipolar disorder. In another aspect, the compoundsdescribed herein may be used to treat, prevent, delay the onset and/ordelay the development of a neuronal disorder. In one aspect, thecompounds described herein may also be used to treat, prevent, delay theonset and/or delay the development of cognitive disorders, psychoticdisorders, neurotransmitter-mediated disorders and/or neuronal disordersfor which the modulation of an aminergic G protein-coupled receptor isbelieved to be or is beneficial.

The invention also provides methods of improving cognitive functionsand/or reducing psychotic effects comprising administering to anindividual in need thereof an amount of a compound of the invention or apharmaceutically acceptable salt thereof effective to improve cognitivefunctions and/or reduce psychotic effects. In a particular variation, amethod of treating schizophrenia is provided, wherein the treatmentprovides an improvement in at least one cognitive function, such as animprovement in a cognitive function in an individual who has or issuspected of having CIAS. In a further variation, a method of treatingschizophrenia is provided wherein the method reduces psychotic effectsassociated with schizophrenia. In one embodiment, a method of treatingschizophrenia is provided wherein the method improves the negativesymptoms of schizophrenia in an individual in need thereof. In oneembodiment, a method of treating schizophrenia is provided wherein themethod improves the positive symptoms of schizophrenia in an individualin need thereof. In a further variation, a method of treatingschizophrenia is provided wherein the method both improves cognitivefunction and reduces psychotic effects in an individual in need thereof.A method of improving one or more negative, positive and disorganizedsymptoms of schizophrenia is also provided, where the method entailsadministering a compound as detailed herein, or a pharmaceuticallyacceptable salt thereof, to an individual in need of such improvement.In one variation, a method of improving at least one negative symptom ofschizophrenia is provided, where the method entails administering acompound as detailed herein, or a pharmaceutically acceptable saltthereof, to an individual in need of such improvement. In anothervariation, a method of improving at least one negative and at least onepositive symptom of schizophrenia is provided, where the method entailsadministering a compound as detailed herein, or a pharmaceuticallyacceptable salt thereof, to an individual in need of such improvement.In yet another variation, a method of improving at least one negativeand at least one disorganized symptom of schizophrenia is also provided,where the method entails administering a compound as detailed herein, ora pharmaceutically acceptable salt thereof, to an individual in need ofsuch improvement. In still another variation, a method of improving atleast one positive and at least one disorganized symptom ofschizophrenia is also provided, where the method entails administering acompound as detailed herein, or a pharmaceutically acceptable saltthereof, to an individual in need of such improvement. In still afurther variation, a method of improving at least one negative, at leastone positive and at least one disorganized symptom of schizophrenia isprovided, where the method entails administering a compound as detailedherein, or a pharmaceutically acceptable salt thereof, to an individualin need of such improvement.

The invention also provides methods of stimulating neurite outgrowthand/or promoting neurogenesis and/or enhancing neurotrophic effects inan individual comprising administering to an individual in need thereofan amount of a compound of the invention or a pharmaceuticallyacceptable salt thereof effective to stimulate neurite outgrowth and/orto promote neurogenesis and/or to enhance neurotrophic effects.

The invention further encompasses methods of modulating an aminergic Gprotein-coupled receptor comprising administering to an individual inneed thereof an amount of a compound of the invention or apharmaceutically acceptable salt thereof effective to modulate anaminergic G protein-coupled receptor.

It is to be understood that methods described herein also encompassmethods of administering compositions comprising the compounds of theinvention.

Methods for Treating, Preventing, Delaying the Onset, and/or Delayingthe Development Cognitive Disorders, Psychotic Disorders,Neurotransmitter-Mediated Disorders and/or Neuronal Disorders

In one aspect, the invention provides methods for treating, preventing,delaying the onset, and/or delaying the development of cognitivedisorders, psychotic disorders, neurotransmitter-mediated disordersand/or neuronal disorders for which the modulation of an aminergic Gprotein-coupled receptor is believed to be or is beneficial, the methodcomprising administering to an individual in need thereof a compound ofthe invention. In some variations, modulation of adrenergic receptorα_(1D), α_(2A), α_(2B), serotonin receptor 5-HT_(2A), 5-HT₆, 5-HT₇,histamine receptor H₁ and/or H₂ is expected to be or is beneficial forthe cognitive disorders, psychotic disorders, neurotransmitter-mediateddisorders and/or neuronal disorders. In some variations, modulation ofadrenergic receptor α_(1D), α_(2A), α_(2B) and a serotonin receptor5-HT₆ receptor is expected to be or is beneficial for the cognitivedisorders, psychotic disorders, neurotransmitter-mediated disordersand/or neuronal disorders. In some variations, modulation of adrenergicreceptor α_(1D), α_(2A), α_(2B), and a serotonin receptor 5-HT₆ receptorand modulation of one or more of the following receptors serotonin5-HT₇, 5-HT_(2A), 5-HT_(2C) and histamine H₁ and H₂ is expected to be oris beneficial for the cognitive disorders, psychotic disorders,neurotransmitter-mediated disorders and/or neuronal disorders. In somevariations, modulation of a dopamine receptor D₂ is expected to be or isbeneficial for the cognitive disorders, psychotic disorders,neurotransmitter-mediated disorders and/or neuronal disorders. In somevariations, modulation of dopamine receptor D_(2L) is expected to be oris beneficial for the cognitive disorders, psychotic disorders,neurotransmitter-mediated disorders and/or neuronal disorders. In somevariations, modulation of a dopamine receptor D₂ is expected to be or isbeneficial for the cognitive disorders, psychotic disorders,neurotransmitter-mediated disorders and/or neuronal disorders. Incertain variations, modulation of a dopamine D_(2L) receptor andserotonin receptor 5-HT_(2A) is expected to be or is beneficial for thecognitive disorders, psychotic disorders, neurotransmitter-mediateddisorders and/or neuronal disorders. In some variations, the cognitivedisorders, psychotic disorders, neurotransmitter-mediated disordersand/or neuronal disorders are treated, prevented and/or their onset ordevelopment is delayed by administering a compound of the invention.

Methods to Improve Cognitive Functions and/or Reduce Psychotic Effects

The invention provides methods for improving cognitive functions byadministering a compound of the invention to an individual in needthereof. In some variations, modulation of one or more of adrenergicreceptor α_(1D), α_(2A), α_(2B), serotonin receptor 5-HT_(2A), 5-HT₆,5-HT₇, histamine receptor H₁ and/or H₂ is desirable or expected to bedesirable to improve cognitive functions. In some variations modulationof α_(1D), α_(2A), α_(2B) adrenergic receptors and a serotonin 5-HT₆receptor is desirable or expected to be desirable to improve cognitivefunctions. In some variations, modulation of α_(1D), α_(2A), α_(2B)adrenergic receptors and serotonin receptor 5-HT₆ and modulation of oneor more of the following receptors: serotonin receptor 5-HT₇, 5-HT_(2A),5-HT_(2C) and histamine receptor H₁ and H₂, is desirable or expected tobe desirable to improve cognitive functions. In another aspect, theinvention encompasses methods to reduce psychotic effects byadministering a compound of the invention to an individual in needthereof. In some embodiments, modulation of a dopamine D₂ receptor isexpected to be or is desirable to reduce psychotic effects. In someembodiments, modulation of a dopamine D_(2L) receptor is expected to beor is desirable to reduce psychotic effects. In some embodiments,modulation of a dopamine D₂ receptor and a serotonin 5-HT_(2A) receptoris expected to be or is desirable to reduce psychotic effects. In someembodiments, modulation of a dopamine D_(2L) receptor and a serotonin5-HT_(2A) receptor is expected to be or is desirable to reduce psychoticeffects. In some variations, a compound of the invention is administeredto an individual in need thereof.

Methods to Stimulate Neurite Outgrowth, Promote Neurogenesis and/orEnhance Neurotrophic Effects

In a further aspect, the invention provides methods of stimulatingneurite outgrowth and/or enhancing neurogenesis and/or enhancingneurotrophic effects comprising administering a compound of theinvention or pharmaceutically acceptable salt thereof under conditionssufficient to stimulate neurite outgrowth and/or to enhance neurogenesisand/or enhance neurotrophic effects to an individual in need thereof. Insome variations, a compound of the invention stimulates neuriteoutgrowth at a potency of about 1 μM as measured in a suitable assaysuch as the assays described herein. In some variations, a compound ofthe invention stimulates neurite outgrowth at a potency of about 500 nMas measured in a suitable assay such as the assays described herein. Insome variations, a compound of the invention stimulates neuriteoutgrowth at a potency of about 50 nM as measured in a suitable assaysuch as the assays described herein. In some variations, a compound ofthe invention stimulates neurite outgrowth at a potency of about 5 nM asmeasured in a suitable assay such as the assays described herein.

Methods to Modulate an Aminergic G Protein-Coupled Receptor

The invention further contemplates methods for modulating the activityof an aminergic G-protein-coupled receptor comprising administering acompound of the invention or pharmaceutically acceptable salt thereofunder conditions sufficient to modulate the activity of an aminergic Gprotein-coupled receptor. In some variations, the aminergic Gprotein-coupled receptor is a α_(1D), α_(2A), α_(2B) adrenergic receptorand a serotonin 5-HT₆ receptor. In some variations, the aminergic Gprotein-coupled receptor is a α_(1D), α_(2A), α_(2B) adrenergic receptorand a serotonin 5-HT₆ and 5-HT₇ receptor. In some variations, theaminergic G protein-coupled receptor is a α_(1D), α_(2A), α_(2B)adrenergic receptor, a serotonin 5-HT₆ and one or more of the followingreceptors: serotonin 5-HT₇, 5-HT_(2A) and 5-HT_(2C) and histamine H₁ andH₂ receptor. In some variations, the aminergic G protein-coupledreceptor is a dopamine D₂ receptor. In some variations, the aminergic Gprotein-coupled receptor is a dopamine D_(2L) receptor. In somevariations, the aminergic G protein-coupled receptor is a dopamine D₂receptor and a serotonin 5-HT_(2A) receptor. In some variations, theaminergic G protein-coupled receptor is a dopamine D_(2L) receptor and aserotonin 5-HT_(2A) receptor. In some variations, the aminergic Gprotein-coupled receptor is a histamine H₁ receptor.

General Synthetic Methods

The compounds of the invention may be prepared by methods as describedin U.S. patent application Ser. No. 12/259,234 filed Oct. 27, 2008 andwhich is incorporated herein by reference in its entirety andspecifically with respect to the synthetic methods forpyrido[4,3-b]indoles.

The compounds of the invention may be prepared by a number of processesas generally described below and more specifically in the Exampleshereinafter. In the following process descriptions, the symbols whenused in the formulae depicted are to be understood to represent thosegroups described above in relation to the formulae hereinabove unlessotherwise indicated.

Where it is desired to obtain a particular enantiomer of a compound,this may be accomplished from a corresponding mixture of enantiomersusing any suitable conventional procedure for separating or resolvingenantiomers. Thus, for example, diastereomeric derivatives may beproduced by reaction of a mixture of enantiomers, e.g., a racemate, andan appropriate chiral compound. The diastereomers may then be separatedby any convenient means, for example by crystallization and the desiredenantiomer recovered. In another resolution process, a racemate may beseparated using chiral High Performance Liquid Chromatography.Alternatively, if desired a particular enantiomer may be obtained byusing an appropriate chiral intermediate in one of the processesdescribed.

Chromatography, recrystallization and other conventional separationprocedures may also be used with intermediates or final products whereit is desired to obtain a particular isomer of a compound or tootherwise purify a product of a reaction.

The following abbreviations are used herein: thin layer chromatography(TLC); Hour (h); Minute (min); Second (sec); N-methyl-2-pyrrolidone(NMP); ethanol (EtOH); dimethylsulfoxide (DMSO); N,N-dimethylformamide(DMF); trifluoroacetic acid (TFA); tetrahydrofuran (THF); ethyl acetate(EtOAc); Normal (N); aqueous (aq.); methanol (MeOH); dichloromethane(DCM); retention factor (Rf); room temperature (RT).

General methods of preparing compounds according to the invention aredepicted in exemplified methods below.

General Method 1

To a solution of appropriate 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(1 equiv) in N-methyl-2-pyrrolidone is added KOH (7 equiv). The reactionmixture is stirred at RT for 20 min. A solution of appropriate2-bromo-1-(aryl)ethanone (1 equiv) in N-methyl-2-pyrrolidone is addeddropwise and stirring is continued for additional 2-4 h. The reaction ismonitored by LCMS and TLC. The reaction mixture is diluted by addingwater and extracted with EtOAc. The organic layer is washed with water,dried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue is purified by silica gel chromatography.

General Method 2

Appropriate2-(3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-arylethanone (1 equiv)is dissolved in anhydrous THF. Grignard reagent (3 equiv) is added to itdropwise at RT under nitrogen atmosphere and reaction mixture is stirredat RT for 1 h. Water is added to the reaction mixture and the product isextracted with EtOAc. The organic layer is washed with water, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue is purified by HPLC.

General Method 3.

Appropriately substituted 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1equiv), appropriately substituted oxirane (2-7.5 equiv) and NaH (1-3equiv) are stirred in DMF at RT for 16 h. The contents are quenched byMeOH and evaporated to dryness. The resulting crude product is purifiedby silica gel chromatography (230-400 mesh) using MeOH-DCM gradientfollowed by reverse-phase chromatography (HPLC).

General Method 4

Appropriate 2-(3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(aryl) EtOH(1 equiv) is dissolved in DCM and the solution is cooled to 0° C.Diethylaminosulfur trifluoride (DAST) (1.5 equiv) is added dropwise andthe reaction mixture is stirred at RT for 2 h. The reaction mixture isdiluted with saturated aqueous NaHCO₃ solution and the organic layer isseparated. The organic layer is dried over anhydrous sodium sulfate andevaporated under reduced pressure. The residue is purified bychromatography on neutral alumina.

General Method 5

Appropriately substituted 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1equiv) is dissolved in DMF (2 mL per mmol) and sodium hydride (2 equiv)is added to it under nitrogen atmosphere. Appropriate2-(bromomethyl)-1,3-dioxolane (1 equiv) is added and the reactionmixture is heated at 100° C. overnight. The reaction mixture is dilutedby adding water and extracted with EtOAc. The organic layer is washedwith water, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue is purified by silica gel chromatography.

General Method 6

Appropriate2-(3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-arylethanone (100 mg, 3mmol) is dissolved in toluene and(carbethoxymethylene)triphenylphosphorane (200 mg, 0.56 mmol) is added.The reaction mixture is heated overnight at 100° C. Solvent is removedunder reduced pressure and the residue is purified by silica gelchromatography.

General Method 7

To a solution of appropriate3-(4-fluorophenyl)-4-(1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)but-2-enoateester in EtOH is added 10% Pd—C (20% w/w). The reaction mixture isstirred under 60 psi H₂ and at RT for 24 h. The catalyst is removed byfiltration and the filtrate is evaporated under reduced pressure toobtain the product.

General Method 8

Appropriate4-(3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(aryl)butanoate esteris suspended in methyl amine and the reaction mixture is heated at 100°C. overnight. The reaction mixture is cooled to RT, diluted with waterand extracted with EtOAc. The organic layer is dried over anhydroussodium sulfate and concentrated under reduced pressure. The product ispurified by silica gel chromatography.

General Method 9

Appropriate4-(3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(4-fluorophenyl)butanoateester is dissolved in MeOH and 1N NaOH is added. The reaction mixture isheated overnight at an oil bath temperature of 50° C. The reactionmixture is cooled to RT, acidified with 1 M HCl and evaporated underreduced pressure. The residue is purified by HPLC.

The methods detailed above may be adapted as known by those of skill inthe art. Particular examples of each General Method are provided in theExamples below.

The following Examples are provided to illustrate but not limit theinvention.

EXAMPLES Example 1 Preparation of2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(4-fluorophenyl)-1-phenylethanol(Compound No. 1)

2-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(4-fluorophenyl)ethanone(168 mg, 0.5 mmol) was dissolved in 10 mL of anhydrous THF. Phenylmagnesium bromide (1.5 mL, 1.5 mmol) was added to it dropwise at RTunder nitrogen atmosphere. The reaction mixture was stirred at RT for 1h. Water (3 mL) was added and the product extracted with EtOAc. Thecombined organic layer was washed with water, dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by HPLC.

Example 2 Preparation of2,8-dimethyl-5-((2-phenyl-1,3-dioxolan-2-yl)methyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound No. 2)

2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2 g, 10 mmol)was dissolved in 20 mL of DMF. The resulting solution was cooled in anice-water bath and sodium hydride (840 mg, 4.2 mmol) was added undernitrogen atmosphere. 2-Bromomethyl-2-phenyl[1,3]dioxolane (2.43 g, 10mmol) was added and the reaction mixture was heated at 100° C.overnight. Water was added and the product was extracted with EtOAc. Theorganic layer was washed with water, dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified bysilica gel chromatography eluting with 0-5% MeOH:DCM.

Example 3 Preparation of5-((2-(4-fluorophenyl)-1,3-dioxolan-2-yl)methyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound No. 3)

2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (4.6 g, 23 mmol)was dissolved in 35 mL of NMP. Sodium hydride (1.93 g, 48.3 mmol) wasadded at RT under nitrogen atmosphere.2-Bromomethyl-2-(4-fluorophenyl)-1,3-dioxolane (6 g, 23 mmol) was addedand the reaction mixture was heated at 100° C. overnight. Water wasadded and the product was extracted with EtOAc. The organic layer waswashed with water, dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was purified by silica gelchromatography eluting with 0-5% MeOH:DCM.

Example 4 Preparation of8-chloro-5-((2-(4-fluorophenyl)-1,3-dioxolan-2-yl)methyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound No. 4)

8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (500 mg, 2.2mmol) was dissolved in 5 mL of NMP. KOH (896 mg, 15 mmol) was added atRT under nitrogen atmosphere and the reaction mixture was stirred for 5min. 2-Bromomethyl-2-(4-fluorophenyl)-1,3-dioxolane (886 mg, 3.4 mmol)was added and the reaction mixture was heated at 100° C. overnight.Water was added and the product was extracted with EtOAc. The organiclayer was washed with water, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel chromatography eluting with 0-2% MeOH:DCM.

Example 5 Preparation of8-chloro-5-((2-(4-chlorophenyl)-1,3-dioxolan-2-yl)methyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound No. 5)

8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1 g, 4.4mmol) was dissolved in 10 mL of NMP. KOH (1.77 g, 31.78 mmol) was addedat RT under nitrogen atmosphere and the reaction mixture was stirred for5 min. 2-Bromomethyl-2-(4-chlorophenyl)-1,3-dioxolane (1.68 mg, 6.81mmol) was added and the reaction mixture was heated at 100° C. for 3 h.Water was added and the product was extracted with EtOAc. The organiclayer was washed with water, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel chromatography eluting with 0-2% MeOH:DCM.

Example 6 Preparation of ethyl4-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(4-fluorophenyl)butanoate(Compound No. 6)

To a solution of ethyl3-(4-fluorophenyl)-4-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)but-2-enoate(112 mg, 0.275 mmol) in EtOH (5 mL) was added 20 mg of 10% Pd/C. Thereaction mixture was stirred at RT under a hydrogen atmosphere at 60 psifor 24 h. The hydrogen pressure was released and the reaction mixturewas filtered through Celite, the catalyst rinsed with EtOH and thefiltrate evaporated under reduced pressure to obtain the product.

Example 7 Preparation of4-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(4-fluorophenyl)butanoicacid (Compound No. 7)

Ethyl4-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(4-fluorophenyl)butanoate(100 mg, 0.24 mmol) was dissolved in 10 mL of MeOH. To this solution wasadded 1N NaOH (5 mL). The reaction mixture was heated in an oil bath ata temperature of 50° C. overnight. The reaction mixture was cooled toRT, acidified with 1M HCl and evaporated to dryness. The residue waspurified by HPLC to obtain 50 mg of product as the TFA salt.

Example 8 Preparation of4-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(4-fluorophenyl)-N-methylbutanamide(Compound No. 8)

Methylamine (1 mL) was added to ethyl4-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(4-fluorophenyl)butanoate(50 mg, 0.122 mmol) and the reaction mixture was heated at 100° C.overnight. The reaction mixture was cooled to RT, diluted with water (5mL) and extracted with EtOAc. The organic layer was dried over anhydroussodium sulfate and concentrated under reduced pressure. The product waspurified by silica gel chromatography (100-200 mesh) eluting with 0-7%MeOH-DCM as eluent.

Example 9 Preparation of5-(2-fluoro-2-(pyridin-4-yl)propyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound No. 9)

1-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-4-yl)propan-2-ol(150 mg) was dissolved in DCM (10 mL) and the solution was cooled to 0to 5° C. Diethylaminosulfur trifluoride (0.15 mL) was added and thereaction mixture was allowed to warm to RT for 30 min. The reactionmixture was quenched with saturated aqueous sodium bicarbonate, theorganic layer was separated, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by HPLC.

Example 10 Preparation of8-chloro-5-(2-fluoro-2-(pyridin-4-yl)propyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(Compound No. 10)

1-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-4-yl)propan-2-ol(300 mg) was dissolved in DCM (10 mL) and the solution was cooled to 0to 5° C. Diethylaminosulfur trifluoride (0.3 mL) was added and thereaction mixture was allowed to warm to RT for 30 min The reactionmixture was quenched with saturated aqueous sodium bicarbonate, theorganic layer was separated, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by HPLC.

Compound Nos. 11-62 can be prepared according to the general syntheticmethods described herein.

Example B1 Determination of the Ability of Compounds of the Invention toBind a Histamine Receptor

Histamine H₁

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant histamine H1 receptor expressed inChinese hamster ovary (CHO) cells (De Backer, M. D. et al., Biochem.Biophys. Res. Comm. 197(3):1601, 1993) in a modified Tris-HCl buffer (50mM Tris-HCl, pH 7.4, 2 mM MgCl₂, 100 mM NaCl, 250 mM Sucrose) was used.Compounds of the invention were incubated with 1.2 nM [³H]Pyrilamine for180 min at 25° C. Non-specific binding was estimated in the presence of1 μM pyrilamine Receptor proteins were filtered and washed, the filterswere then counted to determine [³H]Pyrilamine specifically bound.Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle.Biochemical assay results are presented as the percent inhibition ofspecific binding in Table 2.

Histamine H₂

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant histamine H2 receptor expressed inChinese hamster ovary (CHO) K1 cells (Ruat, M., Proc. Natl. Acad. Sci.USA. 87(5):1658, 1990) in a 50 mM Phosphate buffer, pH 7.4 was used.Compounds of the invention were incubated with 0.1 nM[¹²⁵I]Aminopotentidine for 120 min at 25° C. Non-specific binding wasestimated in the presence of 3 μM Tiotidine. Receptor proteins werefiltered and washed, the filters were then counted to determine[¹²⁵I]Aminopotentidine specifically bound. Compounds were screened at 1μM or lower, using 1% DMSO as vehicle. Biochemical assay results arepresented as the percent inhibition of specific binding in Table 2.

TABLE 2 Binding Data (% Inhibition). Compound Histamine Binding No. H₁H₂ 1 21 74 2 71 89 3 86 96 4 87 96 5 90 98 6 36/39 86 7 −1 5 8 6 22Histamine H₃

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant histamine H₃ receptor expressed inChinese hamster ovary (CHO-K1) cells (Yanai K et al. Jpn. J. Pharmacol.65(2): 107, 1994; Zhu Y et al. Mol. Pharmacol. 59(3): 434, 2001) in amodified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 5 mM MgCl₂, 0.04% BSA)is used. Compounds of invention are incubated with 3 nM[³H]R(−)-α-Methylhistamine for 90 min at 25° C. Non-specific binding isestimated in the presence of 1 μM R(−)-α-Methylhistamine. Receptorproteins are filtered and washed, the filters are counted to determine[³H] R(−)-α-Methylhistamine specifically bound. Compounds are screenedat 1 μM or lower, using 1% DMSO as vehicle. Compounds of the inventionare tested in this biochemical assay and percent inhibition of specificbinding is determined.

Example B2 Determination of the Ability of Compounds of the Invention toBind a Imidazoline I₂ Receptor

Central Imidazoline I₂

To evaluate in radioligand binding assays the activity of compounds ofthe invention, rat central imidazoline I₂ receptor obtained from WistarRat cerebral cortex (Brown, C. M. et al., Br. J. Pharmacol. 99:803,1990) in a modified Tris-HCl buffer (50 mM Tris-HCl buffer, pH 7.4, 0.5mM EDTA) is used. Compounds of the invention are incubated with 2 nM[³H]Idazoxan for 30 min at 25° C. Non-specific binding is estimated inthe presence of 1 μM Idazoxan. Receptor proteins are filtered andwashed, the filters are then counted to determine [³H]Idazoxanspecifically bound. Compounds are screened at 1 μM or lower, using 1%DMSO as vehicle. Compounds of the invention are tested in thisbiochemical assay and percent inhibition of specific binding isdetermined.

Example B3 Determination of the Ability of Compounds of the Invention toBind an Adrenergic Receptor

Adrenergic α_(1A)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, rat adrenergic α_(1A) receptor obtained from Wistar Ratsubmaxillary glands (Michel, A. D. et al., Br. J. Pharmacol. 98:883,1989) in a modified Tris-HCl buffer (50 mM Tris-HCl buffer, pH 7.4, 0.5mM EDTA) is used. Compounds of the invention are incubated with 0.25 nM[³H]Prozosin for 60 min at 25° C. Non-specific binding is estimated inthe presence of 10 μM phentolamine Receptor proteins are filtered andwashed, the filters are then counted to determine [³H]Prozosinspecifically bound. Compounds of the invention are screened at 1 μM orlower, using 1% DMSO as vehicle. Compounds of the invention are testedin this biochemical assay and percent inhibition of specific binding isdetermined.

Adrenergic α_(1B)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, rat adrenergic α_(1B) receptor obtained from Wistar Ratliver (Garcia-S'ainz, J. A. et al., Biochem. Biophys. Res. Commun.186:760, 1992; Michel A. D. et al., Br. J. Pharmacol. 98:883, 1989) in amodified Tris-HCl buffer (50 mM Tris-HCl buffer, pH 7.4, 0.5 mM EDTA) isused. Compounds of the invention are incubated with 0.25 nM [³H]Prozosinfor 60 min at 25° C. Non-specific binding is estimated in the presenceof 10 μM phentolamine Receptor proteins are filtered and washed, thefilters are then counted to determine [³H]Prozosin specifically bound.Compounds are screened at 1 μM or lower, using 1% DMSO as vehicle.Compounds of the invention are tested in this biochemical assay andpercent inhibition of specific binding is determined.

Adrenergic α_(1D)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant adrenergic α_(1D) receptor expressed inhuman embryonic kidney (HEK-293) cells (Kenny, B. A. et al. Br. J.Pharmacol. 115(6):981, 1995) in a 50 mM Tris-HCl buffer, pH 7.4, wasused. Compounds of invention were incubated with 0.6 nM [³H]Prozosin for60 min at 25° C. Non-specific binding was estimated in the presence of10 μM phentolamine Receptor proteins were filtered and washed, thefilters were then counted to determine [³H]Prozosin specifically bound.Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle.Biochemical assay results are presented as the percent inhibition ofspecific binding in Table 3.

Adrenergic α_(2A)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant adrenergic α_(2A) receptor expressed ininsect Sf9 cells (Uhlen S et al. J. Pharmacol. Exp. Ther. 271:1558,1994) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 12.5 mMMgCl₂, 2 mM EDTA) was used. Compounds of invention were incubated with 1nM [³H]MK-912 for 60 min at 25° C. MK912 is(2S-trans)-1,3,4,5′,6,6′,7,12b-octahydro-1′,3′-dimethyl-spiro[2H-benzofuro[2,3-a]quinolizine-2,4′(1′H)-pyrimidin]-2′(3′H)-onehydrochloride Non-specific binding was estimated in the presence of 10μM WB-4101 (2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxanehydrochloride). Receptor proteins were filtered and washed, the filterswere then counted to determine [³H]MK-912 specifically bound. Compoundswere screened at 1 μM or lower, using 1% DMSO as vehicle. Biochemicalassay results are presented as the percent inhibition of specificbinding in Table 3.

Adrenergic α_(2B)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant adrenergic α_(2B) receptor expressed inChinese hamster ovary (CHO-K1) cells (Uhlen S et al. Eur. J. Pharmacol.343(1):93, 1998) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4,12.5 mM MgCl₂, 1 mM EDTA, 0.2% BSA) was used. Compounds of the inventionwere incubated with 2.5 nM [³H]Rauwolscine for 60 min at 25° C.Non-specific binding was estimated in the presence of 10 μM Prozosin.Receptor proteins were filtered and washed, the filters were thencounted to determine [³H]Rauwolscine specifically bound. Compounds werescreened at 1 μM or lower, using 1% DMSO as vehicle. Biochemical assayresults are presented as the percent inhibition of specific binding inTable 3.

Adrenergic α_(2C)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant adrenergic α_(2C) receptor expressed ininsect Sf9 cells (Uhlen S et al. J. Pharmacol. Exp. Ther. 271:1558,1994) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 12.5 mMMgCl₂, 2 mM EDTA) is used. Compounds of the invention are incubated with1 nM [³H]MK-912 for 60 min at 25° C. Non-specific binding is estimatedin the presence of 10 μM WB-4101. Receptor proteins are filtered andwashed, the filters are then counted to determine [³H]MK-912specifically bound. Compounds are screened at 1 μM or lower, using 1%DMSO as vehicle. Compounds of the invention are tested in thisbiochemical assay and percent inhibition of specific binding isdetermined.

Example B4 Determination of the Ability of Compounds of the Invention toBind a Dopamine Receptor

Dopamine D_(2L)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant dopamine D_(2L) receptor expressed inChinese hamster ovary (CHO) cells (Grandy, D. K. et al. Proc. Natl.Acad. Sci. USA. 86:9762, 1989; Hayes, G. et al., Mol. Endocrinol. 6:920,1992) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 1.4 mMAscorbic Acid, 0.001% BSA, 150 mM NaCl) was used. Compounds of theinvention were incubated with 0.16 nM [³H]Spiperone for 120 min at 25°C. Non-specific binding was estimated in the presence of 10 μMHaloperidol. Receptor proteins were filtered and washed, the filterswere then counted to determine [³H]Spiperone specifically bound.Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle.Biochemical assay results are presented as the percent inhibition ofspecific binding in Table 3.

TABLE 3 Percent Inhibition of ligand binding to aminergic G protein-coupled receptors by compounds of the invention: Compound Adrenergic (1μM) Dopamine (1 μM) No. a_(1D) a_(2A) a_(2B) D_(2L) 1 42 94 95 6 2 56 91103 51 3 60 92 106 45 4 35 95 103 58 5 16 95 97 53 6 106 95 95 24/31 721 9 12 −10 8 87 63 72 14

Example B5 Determination of the Ability of Compounds of the Invention toBind a Serotonin Receptor

Serotonin (5-Hydroxytryptamine) 5-HT_(1A)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine)5-HT_(1A) receptor expressed in Chinese hamster ovary (CHO-K1) cells(Martin G R and Humphrey P P A. Neuropharmacol. 33:261, 1994; May J A,et al. J. Pharmacol. Exp. Ther. 306(1): 301, 2003) in a modifiedTris-HCl buffer (50 mM Tris-HCl, pH 7.4, 0.1% Ascorbic Acid, 0.5 mMEDTA, 10 mM MgSO₄) is used. Compounds of invention are incubated with1.5 nM [³H]8-OH-DPAT for 60 min at 25° C. Non-specific binding isestimated in the presence of 10 μM Metergoline. Receptor proteins arefiltered and washed, the filters are then counted to determine[³H]8-OH-DPAT specifically bound. Compounds are screened at 1 μM orlower, using 1% DMSO as vehicle. Compounds of the invention are testedin this biochemical assay and percent inhibition of specific binding isdetermined.

Serotonin (5-Hydroxytryptamine) 5-HT_(1B)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, serotonin (5-Hydroxytryptamine) 5-HT_(1B) receptor fromWistar Rat cerebral cortex (Hoyer et al. Eur. J. Pharmacol. 118: 1,1985; Pazos et al. Eur. J. Pharmacol. 106: 531, 1985) in a modifiedTris-HCl buffer (50 mM Tris-HCl, pH 7.4, 154 mM NaCl, 10 μM Pargyline,30 μM Isoprenaline) is used. Compounds of invention are incubated with10 μM [¹²⁵I]Cyanopindolol for 90 min at 37° C. Non-specific binding isestimated in the presence of 10 μM Serotonin (5-HT). Receptor proteinsare filtered and washed, the filters are then counted to determine[¹²⁵I]Cyanopindolol specifically bound. Compounds are screened at 1 μMor lower, using 1% DMSO as vehicle. Compounds of the invention aretested in this biochemical assay and percent inhibition of specificbinding is determined.

Serotonin (5-Hydroxytryptamine) 5-HT_(2A)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine)5-HT_(2A) receptor expressed in Chinese hamster ovary (CHO-K1) cells(Bonhaus, D. W. et al. Br. J. Pharmacol. 115:622, 1995; Saucier, C. andAlbert, P. R., J. Neurochem. 68: 1998, 1997) in a 50 mM Tris-HCl buffer,pH 7.4, was used. Compounds of the invention were incubated with 0.5 nM[³H]Ketanserin for 60 min at 25° C. Non-specific binding was estimatedin the presence of 1 μM Mianserin. Receptor proteins were filtered andwashed, the filters were then counted to determine [³H]Ketanserinspecifically bound. Compounds were screened at 1 μM or lower, using 1%DMSO as vehicle. Biochemical assay results are presented as the percentinhibition of specific binding in Table 4.

Serotonin (5-Hydroxytryptamine) 5-HT_(2B)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine)5-HT_(2B) receptor expressed in Chinese hamster ovary (CHO-K1) cells(Bonhaus, D. W. et al., Br. J. Pharmacol. 115:622, 1995) in a modifiedTris-HCl buffer (50 mM Tris-HCl, pH 7.4, 4 mM CaCl₂, 0.1% Ascorbic Acid)is used. Compounds of invention are incubated with 1.2 nM [³H]Lysergicacid diethylamide (LSD) for 60 min at 37° C. Non-specific binding isestimated in the presence of 10 μM Serotonin (5-HT). Receptor proteinsare filtered and washed, the filters are then counted to determine[³H]LSD specifically bound. Compounds are screened at 1 μM or lower,using 1% DMSO as vehicle. Compounds of the invention are tested in thisbiochemical assay and percent inhibition of specific binding isdetermined.

Serotonin (5-Hydroxytryptamine) 5-HT_(2C)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine)5-HT_(2C) receptor expressed in Chinese hamster ovary (CHO-K1) cells(Wolf, W. A. and Schutz, J. S., J. Neurochem. 69:1449, 1997) in amodified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 0.1% Ascorbic Acid, 10μM Pargyline) was used. Compounds of the invention were incubated with 1nM [³H]Mesulergine for 60 min at 25° C. Non-specific binding wasestimated in the presence of 1 μM Mianserin. Receptor proteins werefiltered and washed, the filters were then counted to determine[³H]Mesulergine specifically bound. Compounds were screened at 1 μM orlower, using 1% DMSO as vehicle. Biochemical assay results are presentedas the percent inhibition of specific binding in Table 4.

Serotonin (5-Hydroxytryptamine) 5-HT₃

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine) 5-HT₃receptor expressed in human embryonic kidney (HEK-293) cells (Miller Ket al. Synapase 11:58, 1992; Boess F G et al. Neuropharmacology 36:637,1997) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 1 mM EDTA,5 mM MgCl₂) is used. Compounds of invention are incubated with 0.69 nM[³H]GR-65630 for 60 min at 25° C. Non-specific binding is estimated inthe presence of 10 μM MDL-72222. Receptor proteins are filtered andwashed, the filters are then counted to determine [³H]GR-65630specifically bound. Compounds are screened at 1 μM or lower, using 1%DMSO as vehicle. Compounds of the invention are tested in thisbiochemical assay and percent inhibition of specific binding isdetermined.

Serotonin (5-Hydroxytryptamine) 5-HT₄

To evaluate in radioligand binding assays the activity of compounds ofthe invention, serotonin (5-Hydroxytryptamine) 5-HT₄ receptor fromDuncan Hartley derived Guinea pig striatum (Grossman C J et al. Br. J.Pharmacol. 109:618, 1993) in a 50 mM Tris-HCl, pH 7.4, is used.Compounds of invention are incubated with 0.7 nM [³]GR-113808 for 30 minat 25° C. Non-specific binding is estimated in the presence of 30 μMSerotonin (5-HT). Receptor proteins are filtered and washed, the filtersare then counted to determine [³H]GR-113808 specifically bound.Compounds are screened at 1 μM or lower, using 1% DMSO as vehicle.Compounds of the invention are tested in this biochemical assay andpercent inhibition of specific binding is determined.

Serotonin (5-Hydroxytryptamine) 5-HT_(5A)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine)5-HT_(5A) receptor expressed in Chinese hamster ovary (CHO-K1) cells(Rees, S. et al., FEBS Lett. 355:242, 1994) in a modified Tris-HClbuffer (50 mM Tris-HCl, pH 7.4, 10 mM MgCl₂, 0.5 mM EDTA) is used.Compounds of the invention are incubated with 1.7 nM [³H]Lysergic aciddiethylamide (LSD) for 60 min at 37° C. Non-specific binding isestimated in the presence of 100 μM Serotonin (5-HT). Receptor proteinsare filtered and washed, the filters are then counted to determine[³H]LSD specifically bound. Compounds are screened at 1 μM or lower,using 1% DMSO as vehicle. Compounds of the invention are tested in thisbiochemical assay and percent inhibition of specific binding isdetermined.

Serotonin (5-Hydroxytryptamine) 5-HT₆

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine) 5-HT₆receptor expressed in human HeLa cells (Monsma, F. J. Jr. et al., Mol.Pharmacol. 43:320, 1993) in a modified Tris-HCl buffer (50 mM Tris-HCl,pH 7.4, 150 mM NaCl, 2 mM Ascorbic Acid, 0.001% BSA) was used. Compoundsof the invention were incubated with 1.5 nM [3H]Lysergic aciddiethylamide (LSD) for 120 min at 37° C. Non-specific binding wasestimated in the presence of 5 μM Serotonin (5-HT). Receptor proteinswere filtered and washed, the filters were then counted to determine[3H]LSD specifically bound. Compounds were screened at 1 μM or lower,using 1% DMSO as vehicle. Biochemical assay results are presented as thepercent inhibition of specific binding in Table 4.

Serotonin (5-Hydroxytryptamine) 5-HT₇

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine) 5-HT₇receptor expressed in Chinese hamster ovary (CHO) cells (Roth, B. L. etal., J. Pharmacol. Exp. Ther. 268:1403, 1994; Shen, Y. et al., J. Biol.Chem. 268:18200, 1993) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH7.4, 10 mM MgCl₂, 0.5 mM EDTA) was used. Compounds of invention wereincubated with 5.5 nM [³H] Lysergic acid diethylamide (LSD) for 2 h at25° C. Non-specific binding was estimated in the presence of 10 μMSerotonin (5-HT). Receptor proteins were filtered and washed, thefilters were then counted to determine [³H]LSD specifically bound.Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle.Biochemical assay results are presented as the percent inhibition ofspecific binding in Table 4.

TABLE 4 Percent Inhibition of ligand binding to aminergic G protein-coupled receptors by compounds of the invention: Compound Serotonin (1μM) No. 5-HT_(2A) 5-HT_(2C) 5-HT₆ 5-HT₇ 1 97 99 82 65 2 93 96 102 3 9993 103 99 4 99 101 104 93 5 99 100 85 89 6 95 93 102 93 7 9 14 −3 5 8 8595 63 74

Example B6 Determination of Serotonin (5-Hydroxytryptamine) 5-HT_(2A)Agonist/Antagonist Activity of Compounds of the Invention

To determine for agonist or antagonist activity of compounds of theinvention in functional assays, human recombinant serotonin 5-HT_(2A)receptor expressed in human embryonic kidney (HEK-293) cells (Jerman JC, Brough S J, Gager T, Wood M, Coldwell M C, Smart D and Middlemiss DN. Eur. J. Pharmacol. 414:23-30, 2001) is used. Cells are suspended inDMEM buffer, and distributed in microplates. A cytoplasmic calciumfluorescent indicator which varies proportionally to the free cytosolicCa²⁺ ion concentration is mixed with probenecid in HBSS buffercomplemented with 20 mM HEPES (pH 7.4), added into each well andequilibrated with the cells for 30 min at 37° C. followed by 30 min at22° C.

To measure agonist effects, compounds of the invention, referenceagonist or HBSS buffer (basal control) is added to the cells and changesin fluorescence intensity are measured using a microplate reader. Forstimulated control measurements, 5-HT at 100 nM is added in separateassay wells.

The results are expressed as a percent of the control response to 100 nM5-HT. The standard reference agonist is 5-HT, which is tested in eachexperiment at several concentrations to generate aconcentration-response curve from which its EC₅₀ value is calculated.

To measure antagonist effects, the addition of the compounds of theinvention, reference antagonist or HBSS buffer is followed by theaddition of 3 nM 5-HT or HBSS buffer (basal control) prior thefluorescence measurements. The results are expressed as a percentinhibition of the control response to 3 nM 5-HT. The standard referenceantagonist is ketanserin, which is tested in each experiment at severalconcentrations to generate a concentration-response curve from which itsIC₅₀ value is calculated. Compounds are screened at 3 μM or lower, usingDMSO as vehicle.

Example B7 Determination of Serotonin (5-Hydroxytryptamine) 5-HT₆Agonist/Antagonist Activity of Compounds of the Invention

To determine for agonist or antagonist activity of compounds of theinvention in functional assays, human recombinant 5-HT₆ receptor istransfected in CHO cells (Kohen, R., Metcalf, M. A., Khan, N., Druck,T., Huebner, K., Lachowicz, J. E., Meltzer, H. Y., Sibley, D. R., Roth,B. L. and Hamblin, M. W. “Cloning, characterization and chromosomallocalization of a human 5-HT₆ serotonin receptor,” J. Neurochem. 66: 47,1996) and the activity of compounds of the invention is determined bymeasuring their effects on cAMP production using the Homogeneous TimeResolved Fluorescence (HTRF) detection method. Cells are suspended inHBSS buffer complemented with HEPES 20 mM (pH 7.4) and 500 μM IBMX, andthen distributed in microplates and incubated for 45 min at 37° C. inthe absence (control) or presence of compounds of the invention or thereference agonist or antagonist.

For agonist determinations, stimulated control measurement, separateassay wells contain 10 μM 5-HT. Following incubation, the cells arelysed and the fluorescence acceptor (D2-labeled cAMP) and fluorescencedonor (anti-cAMP antibody labeled with europium cryptate) are added.After 60 min at RT, the fluorescence transfer is measured at lex=337 nmand lem=620 and 665 nm using a microplate reader. The cAMP concentrationis determined by dividing the signal measured at 665 nm by that measuredat 620 nm (ratio).

The results are expressed as a percent of the control response to 10 μM5-HT. The standard reference agonist is 5-HT, which is tested in eachexperiment at several concentrations to generate aconcentration-response curve from which its EC₅₀ value is calculated.

For antagonist determinations, the reference agonist 5-HT is added at afinal concentration of 100 nM. For basal control measurements, separateassay wells do not contain 5-HT. Following 45 min incubation at 37° C.,the cells are lysed and the fluorescence acceptor (D2-labeled cAMP) andfluorescence donor (anti-cAMP antibody labeled with europium cryptate)are added.

After 60 min at RT, the fluorescence transfer is measured as mentionedabove. The results are expressed as a percent inhibition of the controlresponse to 100 nM 5-HT. The standard reference antagonist ismethiothepin.

Example B8 Determination of Dopamine D_(2L) Antagonist Activity ofCompounds

To determine for agonist or antagonist activity of compounds of theinvention in functional assays, human recombinant dopamine D_(2L)receptor stably expressed in Chinese hamster ovary (CHO) cells(Senogles, S E et al. J. Biol. Chem. 265(8):4507, 1990) is used.Compounds of invention are pre-incubated with the membranes (0.1 mg/mL)and 10 mM GDP in modified HEPES buffer (20 mM HEPES, pH 7.4, 100 mMNaCl, 10 mM MgCl₂, 1 mM DTT, 1 mM EDTA) for 20 min and ScintillationProximity Assay (SPA) beads are added for another 60 min at 30° C. Thereaction is initiated by 0.3 nM [³⁵S]GTPγS for an additional 15 minincubation period. Increase of [³⁵S]GTPγS binding by 50% or more (350%)relative to the 1 mM dopamine response by compounds of the inventionindicates possible dopamine D_(2L) receptor agonist activity. Inhibitionof a 10 μM dopamine-induced increase of [³⁵S]GTPγS binding response by50% or more (350%) by compounds of the invention indicates receptorantagonist activity. Compounds are screened at 3 μM or lower, using 0.4%DMSO as vehicle. Assay results are presented as the percent response ofspecific binding.

Example B9 Determination of Dopamine D_(2S) Antagonist Activity ofCompounds of the Invention

To determine for agonist or antagonist activity of compounds of theinvention in functional assays, human recombinant dopamine D_(2S)receptor stably expressed in Chinese hamster ovary (CHO) cells(Gilliland S L and Alper R H. Naunyn-Schmiedeberg's Archives ofPharmacology 361:498, 2000) is used. Compounds of invention arepre-incubated with the membranes (0.05 mg/mL) and 3 μM GDP in modifiedHEPES buffer (20 mM HEPES, pH 7.4, 100 mM NaCl, 10 mM MgCl₂, 1 mM DTT, 1mM EDTA) for 20 min and Scintillation Proximity Assay (SPA) beads arethen added for another 60 min at 30° C. The reaction is initiated by 0.3nM [³⁵S]GTPγS for an additional 30 min incubation period. Increase of[³⁵S]GTPγS binding by 50% or more (350%) relative to the 100 μM dopamineresponse by compounds of the invention indicates possible dopamineD_(2S) receptor agonist activity. Inhibition of a 3 μM dopamine-inducedincrease of [³⁵S]GTPγS binding response by 50% or more (350%) bycompounds of the invention indicates receptor antagonist activity.Compounds are screened at 3 μM or lower, using 0.4% DMSO as vehicle.Assay results are presented as the percent response of specific binding.

Example B10 Determination for Agonist or Antagonist Activity ofCompounds of the Invention in a Histamine H1 Functional Assay

To determine for agonist or antagonist activity of compounds of theinvention in functional assays, human recombinant Histamine H₁ receptorexpressed in human embryonic kidney (HEK-293) cells (Miller, T. R.,Witte, D. G., Ireland, L. M., Kang, C. H., Roch, J. M., Masters, J. N.,Esbenshade, T. A And Hancock, A. A. J. Biomol. Screen. 4: 249-258, 1999)is used. Cells are suspended in DMEM buffer, and then distributed inmicroplates. A cytoplasmic calcium fluorescent indicator—which variesproportionally to the free cytosolic Ca²⁺ ion concentration—is mixedwith probenecid in HBSS buffer complemented with 20 mM HEPES (pH 7.4)and is then added into each well and equilibrated with the cells for 30min at 37° C. and then for another 30 min at 22° C. To measure agonisteffects, compounds of the invention, reference agonist or HBSS buffer(basal control) are added to the cells and changes in fluorescenceintensity are measured using a microplate reader. For stimulated controlmeasurements, histamine at 10 μM is added in separate assay wells.

The results are expressed as a percent of the control response to 10 μMhistamine. The standard reference agonist is histamine, which is testedin each experiment at several concentrations to generate aconcentration-response curve from which its EC₅₀ value is calculated.

To measure antagonist effects, the addition of the compounds of theinvention, reference antagonist or HBSS buffer is followed by theaddition of 300 nM histamine or HBSS buffer (basal control) prior thefluorescence measurements. The results are expressed as percentinhibition of the control response to 300 nM histamine. The standardreference antagonist is ketanserin, which is tested in each experimentat several concentrations to generate a concentration-response curvefrom which its IC₅₀ value is calculated. Compounds are screened at 3 μMor lower, using DMSO as vehicle.

Example B11 Increase of Neurite Outgrowth

Neurite Outgrowth in Cortical Neurons

Compounds are tested to determine their ability to stimulate neuriteoutgrowth of cortical neurons. Standard methods are used to isolatecortical neurons. For the isolation of primary rat cortical neurons, thefetal brain from a pregnant rat at 17 days of gestation is prepared inLeibovitz's medium (L15; Gibco). The cortex is dissected out, and themeninges are removed. Trypsin (Gibco) is used to dissociate cortical Cwith DNAse I. The cells are triturated for 30 min with a pipette inDulbecco's Modified Eagle Media (“DMEM”; Gibco) with 10% Fetal BovineSerum (“FBS”) (Gibco) and centrifuged at 350×g for 10 min at RT. Thecells are suspended in Neurobasal medium supplemented with 2% B27(Gibco) and 0.5 mM L-glutamine (Gibco). The cells are maintained at30,000 cells per well of poly-L-lysine coated plates at 37° C. in 5%CO₂-95% air atmosphere. After adhesion, a vehicle control or compoundsof the invention are added at different concentrations to the medium.BDNF (50 ng/mL) is used as a positive control for neurite growth. Aftertreatment, cultures are washed in phosphate-buffered saline (“PBS”;Gibco) and fixed in glutaraldehyde 2.5% in PBS. Cells are fixed after 3days growth. Several pictures (˜80) of cells with neurites are taken percondition with a camera. The length measurements are made by analysis ofthe pictures using software from Image-Pro Plus (France). The resultsare expressed as mean (s.e.m.). Statistical analysis of the data isperformed using one way analysis of variance (ANOVA).

Neurite Outgrowth in Rat Mixed Cortical Cultures

Cortical mixed cultures are prepared from E18 Wistar rat embryos. Thecortices are dissected out and the tissue is cut to small pieces. Thecells are separated by 15-min incubation with DNase and papain. Thecells are collected by centrifugation (1500 rpm, 5 min). The tissue istriturated with a pipette and the cells are plated using the micro-isletprotocol (20,000 cells in 25 μL medium) on poly-L-lysine coated 48wells, in MEM supplemented with 2 mM glutamine, 0.1 μg/mL gentamicin,10% heat-inactivated fetal bovine serum (FBS-HI) and 10%heat-inactivated horse serum (HS-HI). After the cells attach to thewell, 250 μL medium is added to the wells. Four hours after plating themedium is changed to fresh medium (MEM with supplements and 5% HS-HI)containing test compound at 0.5, 5 and 50 nM concentrations. As positivecontrols BDNF (50, 100 and/or 150 ng/mL), and/or NGF (50 ng/mL and/or100 ng/mL) are used. After 2 days in vitro, the cell's conditioned mediaare collected from plates before fixing the cells. The media samples arecentrifuged 13,000 rpm 3 min to get rid of cell debris. The samples arestored at −20° C. for later analysis. Cells are formaldehyde-fixed andprocessed for immunocytochemistry. BDNF levels in the conditioned mediaare determined with a BDNF ELISA using the manufacturers (Promega, BDNFEmax® ImmunoAssay System, catalog number: G7610) instructions.

The cultures are fixed with 4% formaldehyde in 0.01M PBS for 30 min andwashed once with PBS. The fixed cells are first permeabilized andnon-specific binding is blocked by a 30-min incubation with blockingbuffer containing 1% bovine serum albumin and 0.3% Triton X-100 in PBS.Rabbit anti-MAP-2 (dilution 1:1000, AB5622, Chemicon, in blockingbuffer) is used as a primary antibody. The cells are incubated with theprimary antibody for 48 h at +4° C., washed with PBS and incubated withsecondary antibody goat anti-rabbit IgG conjugated to Alexa Fluor568(1:200, A11036, Molecular Probes) for 2 h at RT. The immunopositivecells are visualized by a fluorescence microscope equipped withappropriate filter set, and documented by a high resolution imagecapturing. The number of cells per field (4 field per well) are counted,and the neurite outgrowth is quantified using Image Pro Plus software.

The number of wells per compound concentration used is 6 (n=6). All dataare presented as mean±standard deviation (SD) or standard error of mean(SEM), and differences are considered to be statistically significant atthe p<0.05 level. Statistical analysis is performed using StatsDirectstatistical software. Differences between group means are analyzed byusing 1-way-ANOVA followed by Dunnet's test (comparison to the vehicletreated group).

Example B12 Use of an In Vivo Model to Evaluate the Ability of Compoundsto Enhance Cognition, Learning and Memory in Scopolamine Treated Rats

The two-trial object recognition paradigm developed by Ennaceur andDelacour in the rat is used as a model of episodic/short-term memory.Ennaceur, A., and Delacour, J. (1988), Behav. Brain Res. 31:47-59. Theparadigm is based on spontaneous exploratory activity of rodents anddoes not involve rule learning or reinforcement. The novel objectrecognition paradigm is sensitive to the effects of ageing andcholinergic dysfunction. See, e.g., Scali, C., et al., (1994), Neurosci.Letts. 170:117-120; and Bartolini, L., et al., (1996), Biochem. Behav.53:277-283.

Male Sprague-Dawley rats between six and seven weeks old, weighingbetween 220-300 grams are obtained, e.g., from Centre d'Elevage (RueJanvier, B. P. 55, Le Genest-Saint-Isle 53940, France). The animals arehoused in groups of 2 to 4 in polypropylene cages (with a floor area of1032 cm²) under standard conditions: at RT (22±2° C.), under a 12 hlight/12 h dark cycle, with food and water provided ad libitum. Animalsare permitted to acclimate to environmental conditions for at least 5days before the experiment begins, and are numbered on their tails withindelible marker.

The experimental arena is a square wooden box (60 cm×60 cm×40 cm)painted dark blue, with 15 cm×15 cm black squares under a clearplexiglass floor. The arena and objects placed inside the arena arecleaned with water between each trial to eliminate any odor trails leftby rats. The arena is placed in a dark room illuminated only by halogenlamps directed towards the ceiling in order to produce a uniformly dimlight in the box of approximately 60 lux. The day before testing,animals are allowed to freely explore the experimental arena for 3 minin the presence of two objects (habituation). Animals to be tested areplaced in the experimental room at least 30 min before testing.

Novel object recognition test is comprised of two trials separated by aninterval of 120 min or 24 h. When agents that disrupt memory such as thecholinergic antagonist scopolamine are used an inter-trial interval of120 min is preferred. Alternatively a 24 h inter-trial interval is usedwhen studying effect of natural forgetting on novel object recognitiontask. During the first, or acquisition, trial (T₁), rats are placed inthe arena, where two identical objects have been previously placed. Thetime required for each animal to complete 15 sec of object explorationis determined, with a cut-off time of 4 min. Exploration is consideredto be directing the nose at a distance less than 2 centimeters (“cm”)from the object and/or touching the object. During the second, ortesting, trial (T₂), one of the objects presented in the first trial isreplaced with an unknown or novel object, while the second, familiarobject is left in place. Rats are placed back in the arena for 3 min,and exploration of both objects is determined. Locomotor activity ofrats (number of times rats cross grid lines visible under the clearplexiglass floor) is scored for during T₁ and T₂. At the conclusion ofthe experiments, the rats are sacrificed by an overdose of pentobarbitalgiven intraperitoneally.

The following parameters are measured as part of the novel objectrecognition task: (1) time required to achieve 15 sec of objectexploration during T₁; (2) locomotor activity during T₁ (number ofcrossed lines); (3) time spent in active exploration of the familiarobject during T₂ (T_(Familiar)); (4) time spent in active exploration ofthe novel object during T₂ (T_(Novel)); and (5) locomotor activityduring T₂ (number of crossed lines). The difference between time spentin active exploration of the novel object during T₂ and time spent inactive exploration of the familiar object during T₂ (ΔT_(Novel)−T_(Familiar)) is evaluated. The percent of animals in eachgroup with T_(Novel)−T_(Familiar) greater than or equal to 5 sec is alsoderived; described as percent of good learners.

Animals not meeting a minimal level of object exploration are excludedfrom the study as having naturally low levels of spontaneousexploration. Thus, only rats exploring the objects for at least five sec(T_(Novel)+T_(Familiar)>5 sec) are included in the study.

Animals are randomly assigned to groups of 14. Compounds of theinvention and controls are administered to animals the groups asfollows: Solutions of compounds are prepared freshly each day at aconcentration of 0.25 mg/mL using purified water or saline as vehicle.Donepezil, used as a positive control, and scopolamine are administeredsimultaneously in a single solution of saline (5 mL/kg) prepared freshlyeach day. Scopolamine is purchased from Sigma Chemical Co. (Catalog No.S-1875; St. Quentin Fallavier, France) is dissolved in saline to aconcentration of 0.06 mg/mL.

Donepezil or its vehicle and scopolamine are administeredintraperitoneally 40 min before the acquisition trial (T₁). Compounds ortheir vehicle are administered by gavage 25 min before the acquisitiontrial (T₁), e.g., 5 min after administration of scopolamine. The volumeof administration is 5 mL/kg body weight for compounds administeredintraperitoneally, and 10 mL/kg for compounds administered orally.Recognition scores and percent of good learners for compounds of theinvention are determined.

Example B13 Use of an In Vivo Model to Determine the Ability ofCompounds to Treat, Prevent and/or Delay the Onset and/or theDevelopment of Schizophrenia in PCP Treated Animals

In vivo models of schizophrenia can be used to determine the ability ofthe compounds described herein to treat and/or prevent and/or delay theonset and/or the development of schizophrenia.

One exemplary model for testing the activity of one or more compoundsdescribed herein to treat and/or prevent and/or delay the onset and/ordevelopment of schizophrenia employs phencyclidine (PCP), which isadministered to the animal (e.g., non-primate (rat) or primate(monkey)), resulting in dysfunctions similar to those seen inschizophrenic humans. See Jentsch et al., 1997, Science 277:953-955 andPiercey et al., 1988, Life Sci. 43(4):375-385). Standard experimentalprotocols may be employed in this or in other animal models. Oneprotocol involves PCP-induced hyperactivity.

Male mice (various strains, e.g., C57B1/6J) from appropriate vendor (forexample, Jackson Laboratories (Bar Harbor, Me.) are used. Mice arereceived at 6-weeks of age. Upon receipt, mice are assigned uniqueidentification numbers (tail marked) and are group housed with 4mice/cage in OPTI mouse ventilated cages. All animals remain housed ingroups of four during the remainder of the study. All mice areacclimated to the colony room for at least two weeks prior to testingand are subsequently tested at an average age of 8 weeks. During theperiod of acclimation, mice are examined on a regular basis, handled,and weighed to assure adequate health and suitability. Animals aremaintained on a 12/12 light/dark cycle. The room temperature ismaintained between 20 and 23° C. with a relative humidity maintainedbetween 30% and 70%. Food and water are provided ad libitum for theduration of the study. In each test, animals are randomly assignedacross treatment groups.

The open filed (OF) test assesses locomotor behavior, e.g., to measuremouse locomotor activity at baseline and in response to pharmacologicalagents. The open field chambers are Plexiglas square chambers(27.3×27.3×20.3 cm; Med Associates Inc., St Albans, Vt.) surrounded byinfrared photobeams (16×16×16) to measure horizontal and verticalactivity. The analysis is configured to divide the open field into acenter and periphery zone such that the infrared photobeams allowmeasurement of activity in the center and periphery of the field.Distance traveled is measured from horizontal beam breaks as the mousemoved whereas rearing activity is measured from vertical beam breaks.

Mice (10 to 12 animals per treatment group) are brought to the activityexperimental room for at least 1 h acclimation to the experimental roomconditions prior to testing. Eight animals are tested in each run. Miceare administered vehicle (e.g., 10% DMSO or 5% PEG200 and 1% Tween 80),compound of the invention, clozapine (positive control, 1 mg/kg ip) andplaced in the OF chambers for 30 min following which they are injectedwith either water or PCP and placed back in the OF chambers for a 60-minsession. At the end of each OF test session the OF chambers arethoroughly cleaned.

PCP Hyperactivity Mouse Model of Schizophrenia

The test compound at the desired dose is dissolved in appropriatevehicle, e.g., 5% PEG200, 1% Tween80 and administered orally 30 minprior to PCP injection. Clozapine (1 mg/kg) is dissolved in 10% DMSO andadministered i.p. 30 min prior to PCP injection. PCP (5 mg/kg) isdissolved in sterile injectable saline solution and administered i.p.

Data are analyzed by analysis of variance (ANOVA) followed by post-hoccomparisons with Fisher Tests when appropriate. Baseline activity ismeasured during the first 30 min of the test prior to PCP injection.PCP-induced activity is measured during the 60 min following PCPinjection. Statistical outliers that fell above or below 2 standarddeviations from the mean are removed from the final analyses. An effectis considered significant if p<0.05. Total distances traveled and totalrearing following PCP administration are compared between groups treatedwith compounds and groups treated with vehicle and positive controlclozapine.

PCP Hyperactivity Mouse Model of Schizophrenia

Protocol is as described above with the exception of the treatmentgroups which are as follows: All injections are at a dose volume of 10mL/kg. The test compound at the desired dose is dissolved in PhosphateBuffered Saline (PBS) and administered orally 30 min. prior to PCPinjection. Clozapine (0.5 and 1.0 mg/kg) is dissolved in 10% DMSO andadministered i.p. 30 min. prior to Phencyclidine (PCP) injection. PCP(5.0 mg/kg) is dissolved in sterile injectable saline and administeredi.p. Total distances traveled for is determined.

Example B14 Use of an In Vivo Model to Determine the Ability ofCompounds to Treat, Prevent and/or Delay the Onset and/or theDevelopment of Schizophrenia in Amphetamine Treated Animals

Male mice (various strains e.g., C57B1/6J) from appropriate supplier(for example Jackson Laboratories, Bar Harbor, Me.) are used. Micetypically are received at 6-weeks of age. Mice are acclimated to thecolony room for at least two weeks prior to testing. During the periodof acclimation, mice are examined on a regular basis, handled, andweighed to assure adequate health and suitability and maintained on a12/12 light/dark cycle. The room temperature is maintained between 20and 23° C. with a relative humidity maintained between 30% and 70%. Foodand water are provided ad libitum for the duration of the study. In eachtest, animals are randomly assigned between treatment groups.

The open field test (OF) is used to assess motor activity. The openfield chambers are plexiglass square chambers (e.g., 27.3×27.3×20.3 cm;Med Associates Inc., St Albans, Vt.) surrounded by infrared photobeamsources (16×16×16). The enclosure is configured to split the open fieldinto a center and periphery zone and the photocell beams are set tomeasure activity in the center and in the periphery of the OF chambers.Horizontal activity (distance traveled) and vertical activity (rearing)are measured from consecutive beam breaks.

On the day of testing, animals are brought to the experimental room forat least 1 h acclimation prior to start of treatment. Animals areadministered with vehicle, haloperidol (positive control, 0.1 mg/kg ip)or test compound and placed in the OF. The time of administration ofclient compound to each animal is recorded. Baseline activity isrecorded for 30 min following which mice receive amphetamine (4 mg/kg)or water and are placed back in the OF chambers for a 60-min session. Atthe end of each open field test session the OF chambers are thoroughlycleaned. Typically ten to twelve mice are tested in each group. Testcompound doses typically range from 0.01 mg/kg to 60 mg/kg.

Data are analyzed by analysis of variance (ANOVA) followed by post-hoccomparisons with Fisher Tests when appropriate. Baseline activity ismeasured during the first 30 min of the test prior to amphetamineinjection. Amphetamine-induced activity is measured during the 60 minfollowing amphetamine injection. Statistical outliers that fall above orbelow 2 standard deviations from the mean are removed from the finalanalyses. An effect is considered significant if p<0.05. Total distancetraveled and total rearing following amphetamine administration arecompared between groups treated with compound and groups treated withvehicle and positive control haloperidol.

Example B15 Use of the In Vivo Conditioned Avoidance Response (CAR)Model to Determine the Ability of Compounds to Treat, Prevent and/orDelay the Onset and/or the Development of Schizophrenia

All currently approved antipsychotic agents (typical and atypical) areknown to have the ability to selectively suppress conditioned avoidanceresponse (CAR) behavior in the rat. This evidence makes CAR one of theprimary tests to assess antipsychotic activity of novel compounds.

Rats (various strains, 2 months of age) are trained and tested in acomputer-assisted, two-way active avoidance apparatus (shuttle box).This box consists of two compartments of equal size divided by astainless steel partition containing an opening of 7×7 cm. Eachcompartment is equipped with an electrified grid floor made of stainlesssteel rods spaced 1 cm apart. Rats trained to avoid the foot shock areplaced each day in the shuttle box for a 4 min habituation periodfollowed by 30 trials spaced by inter-trial interval varying at randombetween 20 and 30 sec. Each trial consists of a 10-sec stimulus light(conditioned stimulus, CS) followed by a 10-sec foot shock(unconditioned stimulus, US) in presence of the light presented in thecompartment where the rat is located. If the animal leaves thecompartment prior to the delivery of the foot shock, the response isconsidered an avoidance response. If the rat does not change compartmentduring the 10-sec light period and during the 10-sec shock+light period,an escape failure is recorded. This test requires animals to be trained5 days/week. On each training day, rats are submitted to one trainingsession of 30-trials. Treatment with test compound is initiated onlywhen rats reach an avoidance performance of at least 80% on at least twoconsecutive training sessions. The test compound is administered orallyat various doses and various pre-treatment times (depending uponspecific pharmacokinetic properties).

Compounds with antipsychotic profile inhibit conditioned avoidanceresponses with or without increases in escape failures. Statisticalanalysis is performed using a Friedman two-way ANOVA by ranks followedby the Wilcoxon matched-pairs signed-ranks test to test each dose of thetest compound administered versus vehicle control treated rats.

Example B16 An Animal Model of the Negative Symptoms of Schizophrenia:Subchronic PCP-Induced Social Interaction Deficits

Phencyclidine (PCP) administered to humans as well to experimentalanimals induces full-spectrum of schizophrenia symptoms, includingnegative symptoms and cognitive deficits. A major symptom ofschizophrenia is considered to be social isolation/withdrawal as part ofthe cluster of negative symptoms. Subchronic treatment with PCP in ratsleads to the development of clear signs of social withdrawal as measuredby deficits in the interaction time with a cage intruder rat. MaleSprague Dawley rats (about 150 g, obtained from different vendors, forexample Harlan, Ind.) are used in this study. Upon receipt, rats aregroup housed in OPTI rat ventilated cages. Rats are housed in groups of2-3 per cage for the remainder of the study. During the period ofacclimation, rats are examined on a regular basis, handled, and weighedto assure adequate health and suitability. Rats are maintained on a12/12 light/dark cycle with the light on at 7:00 a.m. The roomtemperature is maintained between 20-23° C. with a relative humiditymaintained between 30-70%. Food and water are provided ad libitum forthe duration of the study. Animals are randomly assigned acrosstreatment groups and balanced by age.

For five days prior to test, rats are injected twice daily with eitherPCP (2 mg/kg; s.c) or saline (s.c). On day 6 and following a 30 minpretreatment with vehicle, clozapine (2.5 mg/kg ip dissolved in 5%PEG:5% Tween 80) as positive control and test compound at desired dosedissolved in appropriate vehicle, a pair of rats, unfamiliar to eachother, receiving the same treatment are placed in a white plexiglas openfield arena (24″×17″×8″) and allowed to interact with each other for 6min. Social interactions (‘SI’) include: sniffing the other rat;grooming the other rat; climbing over or under or around the other rat;following the other rat; or exploring the ano-genital area of the otherrat. Passive contact and aggressive contact are not considered a measureof social interaction. The time the rats spent interacting with eachother during the 6 min test is recorded by a trained observer. Thesocial interaction chambers are thoroughly cleaned between the differentrats. Data are analyzed by analysis of variance (ANOVA) followed bypost-hoc analysis (e.g., Fischer, Dunnett) when appropriate. An effectis considered significant if p<0.05.

Example B17 An Animal Model of Extrapyramidal Syndrome (EPS):Measurement of Catalepsy in the Mouse Bar Test

Antipsychotic drugs are known to induce extrapyramidal syndrome (EPS) inanimals and in humans. An animal model considered to be predictive ofEPS is the mouse bar test, which measures cataleptic responses topharmacological agents. Male mice (various strains) from appropriatevendor (for example, Jackson Laboratories (Bar Harbor, Me.) are used.Mice are received at 6-weeks of age. Upon receipt, mice are assignedunique identification numbers (tail marked) and are group housed with 4mice per cage in OPTI mouse ventilated cages. All animals remain housedin groups of four during the remainder of the study. All mice areacclimated to the colony room for at least two weeks prior to testingand are subsequently tested at an average age of 8 weeks. During theperiod of acclimation, mice are examined on a regular basis, handled,and weighed to assure adequate health and suitability. Animals aremaintained on a 12/12 light/dark cycle. The room temperature ismaintained between 20-23° C. with a relative humidity maintained between30-70%. Food and water are provided ad libitum for the duration of thestudy. In each test, animals are randomly assigned across treatmentgroups.

In the mouse bar test, the front paws of a mouse are placed on ahorizontal bar raised 2″ above a Plexiglas platform and time is recordedfor up to 30 sec per trial. The test ends when the animal's front pawsreturn to the platform or after 30 sec. The test is repeated 3 times andthe average of 3 trials is recorded as index of catalepsy. In thesestudies the typical antipsychotic agent haloperidol (2 mg/kg ipdissolved in 10% DMSO) is used as positive control and induces rigidityand catalepsy as measured by time spent holding on the bar. 30 min priorto the trial, test compound at desired dose and dissolved in appropriatevehicle is administered PO, vehicle and positive control haloperidol (2mg/kg ip) are administered to separate groups of mice. Catalepsyresponses are measure 30 min, 1 h and 3 h following treatments. Atrained observer is measuring time spent holding onto the bar during the30 sec trial. Data are analyzed by analysis of variance (ANOVA) followedby post-hoc analysis (e.g., Fischer, Dunnett) when appropriate. Aneffect is considered significant if p<0.05.

Example B18 An Animal Model to Test the Anxiolytic Effects of CompoundsUsing the Elevated Plus Maze (EPM) Test

This study may be used to test the anxiolytic properties of compoundsdetailed herein using the elevated plus maze (EPM) test in C57B1/6Jmice.

Male C57B1/6J mice from Jackson Laboratories (Bar Harbor, Me.) are usedfor the open field study. Mice are received at 6-weeks of age. Uponreceipt, mice are assigned unique identification numbers (tail marked)and are group housed with 4 mice/cage in OPTI mouse ventilated cages.All animals remain housed in groups of four during the remainder of thestudy. All mice are acclimated to the colony room for approximately 2week prior to testing and are subsequently tested at an average age of 8weeks of age. During the period of acclimation, mice and rats areexamined on a regular basis, handled, and weighed to assure adequatehealth and suitability. Animals are maintained on a 12 h/12 h light/darkcycle. The room temperature is maintained between 20 and 23° C. with arelative humidity maintained between 30% and 70%. Chow and water areprovided ad libitum for the duration of the study. In each test, animalsare randomly assigned across treatment groups. All animals areeuthanized after the completion of the study.

Compounds may be dissolved in 5% PEG200/H₂O and administered orally at adose volume of 10 mL/kg 30 min prior to test; 2) Diazepam (2.5 mg/kg) isdissolved in 45% hydroxypropyl-β-cyclodextrin and administered orally ata dose volume of 10 mL/kg 30 min prior to test.

The elevated plus maze test assesses anxiety. The maze (Hamilton Kinder)consists of two closed arms (14.5 h×5 w×35 cm length) and two open arms(6 w×35 l cm) forming a cross, with a square center platform (6×6 cm).All visible surfaces are made of black acrylic. Each arm of the maze isplaced on a support column 56 cm above the floor. Antistatic black vinylcurtains (7′ tall) surround the EPM to make a 5′×5″ enclosure. Animalsare brought to acclimate to the experimental room at least 1 h beforethe test. Mice are placed in the center of the elevated plus maze facingthe closed arm for a 5-min run. All animals are tested once. The timespent, distance traveled and entries in each arm are automaticallyrecorded by a computer. The EPM is thoroughly cleaned after each mouse.

Data are analyzed using analysis of variance (ANOVA) followed byFisher's LSD post hoc analysis when appropriate. An effect is consideredsignificant if p<0.05.

All references throughout, such as publications, patents, patentapplications and published patent applications, are incorporated hereinby reference in their entireties.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is apparent to those skilled in the art that certainminor changes and modifications will be practiced. Therefore, thedescription and examples should not be construed as limiting the scopeof the invention.

The invention claimed is:
 1. A compound of the formula (A):

wherein: R¹ is H, hydroxyl, nitro, cyano, halo, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy; R² isH, hydroxyl, nitro, cyano, halo, C₁-C₈ perhaloalkyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy,C₁-C₈ alkoxy, aryloxy, carboxyl, carbonylalkoxy, thiol, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; X is OH,H, C₁-C₈ unsubstituted alkyl or is taken together with Y to form acyclic moiety of the formula —OCH₂CH₂O—; Y is halo, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈ alkylsubstituted with a carbonylalkoxy, carboxyl or acylamino moiety or istaken together with X to form a cyclic moiety of the formula —OCH₂CH₂O—;and R³ is a substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted cycloalkenyl orsubstituted or a unsubstituted heterocyclyl or a salt or solvatethereof.
 2. The compound of claim 1, or a salt or solvate thereof,wherein X is OH and Y is an unsubstituted aryl.
 3. The compound of claim2, or a salt or solvate thereof, wherein the compound is of the formula(I):

and wherein R¹, R² and R³ are as defined for formula (A).
 4. Thecompound of claim 3, or a salt or solvate thereof, wherein R¹ and R² areindependently an unsubstituted C₁-C₈ alkyl or halo, and R³ is asubstituted aryl or unsubstituted heteroaryl.
 5. The compound of claim4, wherein R¹ is methyl.
 6. The compound of claim 4, wherein R² ismethyl or chloro.
 7. The compound of claim 4, wherein R³ is asubstituted phenyl, or unsubstituted pyridyl, pyrimidinyl, pyrazinyl,imidazolyl, oxazolyl, oxadiazolyl, furanyl, pyrrolyl or thiophenylgroup.
 8. The compound of claim 1, or a salt or solvate thereof, wherethe compound is of the formula (II):

and wherein R¹, R² and R³ are as defined for formula (A).
 9. Thecompound of claim 8, or a salt or solvate thereof, wherein R¹ is anunsubstituted C₁-C₈ alkyl, R² is H, an unsubstituted C₁-C₈ alkyl orhalo, and R³ is a substituted or unsubstituted aryl or a substituted orunsubstituted heteroaryl.
 10. The compound of claim 9, wherein R¹ ismethyl.
 11. The compound of claim 9, wherein R² is methyl or chloro. 12.The compound of claim 9, wherein R³ is a substituted or unsubstitutedphenyl, pyridyl, pyrimidinyl, pyrazinyl, imidazolyl, oxazolyl,oxadiazolyl, furanyl, pyrrolyl or thiophenyl group.
 13. The compound ofclaim 1, or a salt or solvate thereof, wherein X is H and Y is a C₁-C₈alkyl substituted with a carbonylalkoxy, carboxyl or acylamino moiety.14. The compound of claim 13, or a salt or solvate thereof, wherein Y isa moiety selected from the structures:

where R⁴ is a C₁-C₈ unsubstituted alkyl.
 15. The compound of claim 14,or a salt or solvate thereof, wherein the compound is of the formula(III):

and wherein R¹, R² and R³ are as defined for formula (A) and R⁴ is anunsubstituted C₁-C₈ alkyl.
 16. The compound of claim 15, or a salt orsolvate thereof, wherein R¹ is an unsubstituted C₁-C₈ alkyl, R² is anunsubstituted C₁-C₈ alkyl or halo, and R³ is a substituted aryl or asubstituted or unsubstituted heteroaryl.
 17. The compound of claim 16,wherein R¹ is methyl.
 18. The compound of claim 16, wherein R² is methylor chloro.
 19. The compound of claim 16, wherein R³ is a substitutedphenyl, or a substituted or unsubstituted pyridyl, pyrimidinyl,pyrazinyl, imidazolyl, oxazolyl, oxadiazolyl, furanyl, pyrrolyl orthiophenyl group.
 20. The compound of claim 14, or a salt or solvatethereof, wherein the compound is of the formula (IV):

and wherein R¹, R² and R³ are as defined for formula (A).
 21. Thecompound of claim 20, or a salt or solvate thereof, wherein R¹ is anunsubstituted C₁-C₈ alkyl, R² is an unsubstituted C₁-C₈ alkyl or halo,and R³ is a substituted aryl or a substituted or unsubstitutedheteroaryl.
 22. The compound of claim 21, wherein R¹ is methyl.
 23. Thecompound of claim 21, wherein R² is methyl or chloro.
 24. The compoundof claim 21, wherein R³ is a substituted phenyl, or a substituted orunsubstituted pyridyl, pyrimidinyl, pyrazinyl, imidazolyl, oxazolyl,oxadiazolyl, furanyl, pyrrolyl or thiophenyl group.
 25. The compound ofclaim 14, or a salt or solvate thereof, wherein the compound is of theformula (V):

and wherein R¹, R² and R³ are as defined for formula (A).
 26. Thecompound of claim 25, or a salt or solvate thereof, wherein R¹ is anunsubstituted C₁-C₈ alkyl, R² is an unsubstituted C₁-C₈ alkyl or halo,and R³ is a substituted aryl or a substituted or unsubstitutedheteroaryl.
 27. The compound of claim 26, wherein R¹ is methyl.
 28. Thecompound of claim 26, wherein R² is methyl or chloro.
 29. The compoundof claim 26, wherein R³ is a substituted phenyl, or a substituted orunsubstituted pyridyl, pyrimidinyl, pyrazinyl, imidazolyl, oxazolyl,oxadiazolyl, furanyl, pyrrolyl or thiophenyl group.
 30. The compound ofclaim 1, or a salt or solvate thereof, wherein X is an H or anunsubstituted C₁-C₈ alkyl and Y is halo.
 31. The compound of claim 30,or a salt or solvate thereof, wherein the compound is of the formula(VI):

and wherein R¹, R² and R³ are as defined for formula (A).
 32. Thecompound of claim 31, wherein R¹ is an unsubstituted C₁-C₈ alkyl, R² isan unsubstituted C₁-C₈ alkyl or halo, and R³ is an unsubstitutedheteroaryl.
 33. The compound of claim 32, wherein R¹ is methyl.
 34. Thecompound of claim 32, wherein R² is methyl or chloro.
 35. The compoundof claim 32, wherein R³ is an unsubstituted pyridyl, pyrimidinyl,pyrazinyl, imidazolyl, oxazolyl, oxadiazolyl, furanyl, pyrrolyl orthiophenyl group.
 36. The compound of claim 30, or a salt or solvatethereof, wherein the compound is of the formula (VII):

and wherein R¹, R² and R³ are as defined for formula (A).
 37. Thecompound of claim 30 wherein R¹ and R² are independently anunsubstituted C₁-C₈ alkyl and R³ is an unsubstituted heteroaryl.
 38. Thecompound of claim 37, wherein R¹ is methyl.
 39. The compound of claim37, wherein R² is methyl.
 40. The compound of claim 37, wherein R³ is anunsubstituted pyridyl, pyrimidinyl, pyrazinyl, imidazolyl, oxazolyl,oxadiazolyl, furanyl, pyrrolyl or thiophenyl group.
 41. A compoundselected from the group consisting of:2-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(4-fluorophenyl)-1-phenylethanol;2,8-Dimethyl-5-((2-phenyl-1,3-dioxolan-2-yl)methyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;5-((2-(4-Fluorophenyl)-1,3-dioxolan-2-yl)methyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;8-Chloro-5-((2-(4-fluorophenyl)-1,3-dioxolan-2-yl)methyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;8-Chloro-5-((2-(4-chlorophenyl)-1,3-dioxolan-2-yl)methyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;Ethyl4-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(4-fluorophenyl)butanoate;4-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(4-fluorophenyl)butanoicacid;4-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(4-fluorophenyl)-N-methylbutanamide;5-(2-Fluoro-2-(pyridin-4-yl)propyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;8-Chloro-5-(2-fluoro-2-(pyridin-4-yl)propyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;2-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-phenyl-1-(pyridin-4-yl)EtOH;2-Methyl-5-((2-(pyridin-4-yl)-1,3-dioxolan-2-yl)methyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;2,8-Dimethyl-5-((2-(pyridin-3-yl)-1,3-dioxolan-2-yl)methyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;5-((2-(2,4-Difluorophenyl)-1,3-dioxolan-2-yl)methyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;2,8-Dimethyl-5-((2-(pyrimidin-4-yl)-1,3-dioxolan-2-yl)methyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;8-Chloro-5-((2-(2-chlorophenyl)-1,3-dioxolan-2-yl)methyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;8-Chloro-2-methyl-5-((2-(2-methylpyridin-4-yl)-1,3-dioxolan-2-yl)methyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;8-Chloro-5-((2-(2-fluorophenyl)-1,3-dioxolan-2-yl)methyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;8-Chloro-2-methyl-5-((2-(6-methylpyridin-3-yl)-1,3-dioxolan-2-yl)methyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;8-Chloro-2-methyl-5-((2-(3-methylpyridin-4-yl)-1,3-dioxolan-2-yl)methyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;8-Chloro-5-((2-(4-methoxyphenyl)-1,3-dioxolan-2-yl)methyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;Isopropyl4-(8-chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(4-methoxyphenyl)butanoate;Isopropyl4-(8-chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(4-chlorophenyl)butanoate;Isopropyl4-(8-chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(6-methylpyridin-3-yl)butanoate;tert-Butyl4-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(4-fluorophenyl)butanoate;Methyl3-(2,4-difluorophenyl)-4-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)butanoate;Ethyl4-(8-chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(3-methylpyridin-4-yl)butanoate;Ethyl4-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(pyridin-4-yl)butanoate;Ethyl4-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(pyridin-3-yl)butanoate;Ethyl4-(8-chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(pyrimidin-4-yl)butanoate;Ethyl4-(2-ethyl-8-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(2-methylpyridin-4-yl)butanoate;4-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(pyridin-4-yl)butanoicacid;4-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(pyridin-3-yl)butanoicacid;4-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(pyrimidin-4-yl)butanoicacid;4-(2-Ethyl-8-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(2-methylpyridin-4-yl)butanoicacid;4-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(6-methylpyridin-3-yl)butanoicacid;4-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(2-fluorophenyl)butanoicacid;3-(2,4-Difluorophenyl)-4-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)butanoicacid;4-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(3-methylpyridin-4-yl)butanoicacid;4-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(4-methoxyphenyl)butanoicacid;4-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(4-chlorophenyl)butanoicacid;4-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-N-methyl-3-(pyridin-4-yl)butanamide;4-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-N-methyl-3-(pyridin-3-yl)butanamide;4-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-N-methyl-3-(pyrimidin-4-yl)butanamide;4-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-N-methyl-3-(2-methylpyridin-4-yl)butanamide;4-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-N-methyl-3-(6-methylpyridin-3-yl)butanamide;4-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(2-fluorophenyl)-N-methylbutanamide;3-(2,4-Difluorophenyl)-4-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-N-methylbutanamide;4-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-N-methyl-3-(3-methylpyridin-4-yl)butanamide;4-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(4-methoxyphenyl)-N-methylbutanamide;4-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(4-chlorophenyl)-N-methylbutanamide;5-(2-Fluoro-2-(4-fluorophenyl)propyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;8-Chloro-5-(2-(2,4-difluorophenyl)-2-fluoropropyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;5-(2-(4-Chlorophenyl)-2-fluoropropyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;8-Chloro-5-(2-fluoro-2-(pyridin-3-yl)propyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;2-Ethyl-5-(2-fluoro-2-(pyridin-3-yl)propyl)-8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;5-(2-Fluoro-2-(pyrimidin-4-yl)propyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;8-Chloro-5-(2-fluoro-2-(6-methylpyridin-3-yl)propyl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;5-(2-Fluoro-2-(2-methylpyridin-4-yl)propyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;2-Cyclopropyl-5-(2-fluoro-2-(4-methoxyphenyl)propyl)-8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;8-Chloro-5-(2-fluoro-2-(3-methylpyridin-4-yl)propyl)-2-isopropyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;and5-(2-Fluoro-2-(pyridin-4-yl)ethyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole,or a pharmaceutically acceptable salt thereof.
 42. A method ofmodulating a histamine receptor in an individual comprisingadministering to an individual in need thereof a compound according toclaim 1 or
 41. 43. A pharmaceutical composition comprising (a) acompound of claim 1 or 41 or a pharmaceutically acceptable salt thereof,and (b) a pharmaceutically acceptable carrier.
 44. A kit comprising acompound according to claim 1 or 41 and instructions for use.